pink ethanolamine

PINK

Ethanolamine

CIR EXPERT PANEL MEETING

DECEMBER 12-13, 2011

Memorandum

TO: CIR Expert Panel Members and Liaisons FROM: Monice M. Fiume MMF Senior Scientific Analyst/Writer DATE: November 21, 2011 SUBJECT: Draft Tentative Amended Safety Assessment of Ethanolamine and Ethanolamine Salts Enclosed is the draft tentative amended safety assessment on ethanolamine and 12 ethanolamine salts. This is the last safety assessment generated from the split re-review of triethanolamine, diethanolamine, and monoethanolamine. At the September meeting, the Panel finalized the list of ingredients to be included in this re-review. No additional data have been submitted by industry. At this meeting, the Panel should be prepared to develop a discussion and issue a tentative amended conclusion for public comment.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

History: Ethanolamine

Original Report: In 1983, the Expert Panel determined that TEA, DEA, and MEA were safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of ethanolamines should not exceed 5%. Ethanolamine (MEA) should be used only in rinse-off products. Triethanolamine (TEA) and diethanolamine (DEA) should not be used in products containing N-nitrosating agents. December 2010: a formal rereview package was presented to the Panel for the report on TEA, DEA, and MEA

- the report was split into 3 separate documents – DEA, TEA, and MEA, - appropriate new ingredients are to be added to each report

September 26-27, 2011: Re-Review Draft Report The Draft Amended Safety Assessment was presented to the Panel. The assessment was divided into two parts. The first part, entitled Ethanolamine and Related Ethanolamine-Containing Ingredients, included 21 ingredients for consideration for inclusion in the re-review of ethanol-amine Part II, entitled Ethanolamides, was created so that if the Panel determined that the ethanol-amides were not appropriate as part of the re-review of ethanolamine, the Panel could decide that it would be appropriate to re-review isostearamide, myristamide, and stearamide MEA (reviewed in 1995), and include these ethanolamides. The Panel decided that the safety assessment should be split into two separate reports. The following ingredients were deleted from the report on Ethanolamine: All the protein salts, all the alkyl-substituted ethanolamines, and MEA-Dicetearyl Phosphate. December 12-13, 2011: (Draft) Tentative Amended Report The draft Tentative Amended Report on Ethanolamine and Ethanolamine salts was presented to the Panel. No new data were received since the September meeting.



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MEA SEARCH STRATEGY – SCIFINDER – originally searched June 10, 2011

Keep Me Posted Results updates are received weekly

1. Searched all ingredients (except MEA) with CAS #s (38 substances) – 18,866 references a. Refined by document type – 7091 references b. Refined by removing documents in Chinese – 5701 references

2. Searched MEA by CAS # a. Refined by document type – 14229 references b. Refined by year 1980+ - 11440 references

3. Combined results of SS 1 and 2 above - 18968 references 4. Searched all ingredients without CAS #, refined by document type

a. MEA laureth carboxylate – 1 b. MEA steareth carboxylate – 0 c. MEA talloweth – 0 d. MEA hydrolyzed Silk – 0 e. MEA hydrolyzed collagen – 1 f. MEA distearyl phosphate – 0 g. Butylethanolamine – 128 h. Stearamidoethyl ethanolamine phosphate - 0 i. Lysophosphatidylethanolamine – 1982 j. Azelamide MEA – 0 k. Cocamide methyl MEA – 0 l. Deoxyphytantriyl Palmitamide MEA – 0 m. Hydroxyethyl pantotheamide – 0 n. Hydroxylpropyl MEA – 227 o. Myristoyl/palmitoyl/oxostearamide/arachamide DEA – 0 p. Oatamide MEA – 0 q. Palm kernelamide MEA – 0 r. Palmamide MEA – 0 s. Panthothenamide MEA – 0 t. Peanutamide MEA – 0 u. PEG Cocamide MEA – 0

5. Combined SS 3 and all results of SS 4 – 18413 references 6. Applied the following qualifiers to SS 5 above

a. Carcinogen – 593 b. Mutagen – 79 c. Teratogen – 15 d. Developmental toxicity – 56 e. Reproductive toxicity – 8 f. Dermal – 46 g. Toxicology – 728 h. Ocular – 164 i. Irritation – 86 j. Sensitization – 119 k. Photosensitization – 59 l. ADME – 7 m. Dermal absoroption – 4 n. Excretion – 70 o. Pharmacokinetics – 116 p. Kidney renal – 219 q. Choline deficiency – 20 r. Nitrosation – 53

7. Combined all of SS 6 – 2032 references



SEARCH STRATEGY – TEA/DEA/MEA

TOXLINE PUBMED EU Jan 17. 2010 DEA not to be used 111-42-2 & choline 13 15 111-42-2 & carcinogen* 83 21

choline & deficiency & human & cancer

38

TEA restrictions 102-71-6 & carcinogen* 55 11 102-71-6 & choline 5 2 MEA restrictions Jan 25, 2010 102-71-6 OR 111-42-2 (1980-current)

1003 (downloaded 58)

UPDATED SEARCH May 31, 2010

(102-71-6 OR 111-42-2 OR 141-43-5) AND (REPRODUCTI* OR TERATOGEN*) – 142 (Toxline); 41 (DART)

(102-71-6 OR 111-42-2 OR 141-43-5) AND (DEVELOPMENT* OR FETOTOX*) – 378 (Toxline); 47 (DART) (102-71-6 OR 111-42-2 OR 141-43-5) AND TOX* (102-71-6 OR 111-42-2 OR 141-43-5) AND (GENOTOX* OR MUTAGEN* OR CLASTOGEN*) – 286 Toxline); 7 (DART); 9 (CCRIS) (102-71-6 OR 111-42-2 OR 141-43-5) AND (SENSITIZA* OR SENSITIZE* OR SENSITIS* OR IRRIT*) – 306 (Toxline); 6 (DART) (102-71-6 OR 111-42-2 OR 141-43-5) AND (METBOLI* OR ABSORB* OR ABSORP* OR DISTRIBUT* OR EXCRET*) – 403 (Toxline); 18 (DART) 141-43-5 AND CARCINOGEN* – 193 141-43-4 AND CHOLINE - 0

Total Download (most duplicates removed): 1218

UPDATED SEARCH – Sept 21, 2010 – last 12 mos 102-71-8 OR 111-42-2 OR 141-43-5 128 hits/1 useful



Min

utes

BELSITO TEAM – ETHANOLAMINE – SEPT 2011

DR. BELSITO: Nitrosamine, yes. Okay. So, MEA and MEA-containing ingredients, so, this was the one where we had MEA and then the MEA amides. I guess one of the issues, I mean, the MEA I was okay with. Safe as used, the MEA amides, the problem was that we had a whole bunch where we set concentration limits, and, quite honestly, I think they're all probably because that was when the panel was in the mode to set a limit for the highest non-irritating study we had seen and not simply go with when formulated, not to be irritating. But I didn't have the time or the energy to go back and look at all those reports and see why we set limits. If, in fact, that's why those limits were set, then I would be comfortable with going with safe as used when formulated not to be irritating. If there are other tox endpoints that resulted in those limits, I wouldn't be so comfortable. I just don't know.

MS. FIUME: And, actually, because they were split out in all the other reports, I wanted you to easily be able to focus on the MEA-related toxicity data versus what might be pulled out of the report.

DR. BELSITO: Right.

MS. FIUME: So, that was the main reason that I had split it up.

DR. LIEBLER: And I had thought that we were just proceeding along those lines with the MEA, MEA salts is one report, and the MEA amides is another report.

DR. BELSITO: Right.

DR. LIEBLER: So, okay.

DR. BELSITO: Okay, but the salts, say the MEA in the salts, safe as used.

DR. LIEBLER: Yes, except for a couple of deletions, I would think. Again, consistent with our previous stuff with the DEAs, the previous meeting on the DEA, delete the phosphate, the alkyl phosphate, and also to delete the alkyl substitute ethanolamines.

And I just had a question. I haven't seen sulfite in any of our ingredient reviews since I've been on the panel. I don't know, I always think of sulfite allergies in the wine-drinkers, but I don't know, is that a red flag for us? Is that a sulfite, the tail wagging the dog in terms of hazard or any problems there? That's a question more than a suggestion. I don't know. MEA sulfite. Any (inaudible) on that?

DR. BELSITO: Okay, so, which ones are you deleting here?

DR. LIEBLER: So, under the organic substitute, inorganic acid salts, just delete the MEA dicetearyl phosphate.

DR. BELSITO: Okay, but you're leaving the lauryl in?

DR. LIEBLER: Leaving the lauryl and the laureth. Because the sulfates are okay. They're supposed to have been previously reviewed. The lauryl sulfate, laureth sulfate --

DR. BELSITO: Okay.

DR. LIEBLER: -- have previous review, right? The phosphates have not been, right? I think that's correct. And then the alkyl substituted ethanolamines have really different properties.

DR. BELSITO: Get rid of all of them?

DR. LIEBLER: The whole group go.

DR. BELSITO: Okay.

DR. LIEBLER: And we have made --

DR. BELSITO: And the protein salts you're okay with?



DR. LIEBLER: We haven't done the proteins, have we?

MS. FIUME: We haven't done silk for sure.

DR. LIEBLER: I would say delete them because, again, MEA is not the deriving behavior of those compounds, it's the silk or the collagen.

DR. BELSITO: Okay.

MS. FIUME: The collagen has been reviewed, but --

DR. LIEBLER: It has been reviewed, but it's --

MS. FIUME: Yes.

DR. LIEBLER: So, and I think this is consistent with the logic we use when we pair down the DEA salts as an ingredient last time we met.

DR. BELSITO: Okay, so, for inorganic acid salts, we're keeping ethanolamine, obviously, but hydrochloride, deleting MEA sulfite.

DR. LIEBLER: That's a question. Is there a problem with sulfite? Is there any issue that -- otherwise, I'll keep it in. I just wanted to know. I just -- okay, nobody's registering on that, so, fine, keep it.

DR. BELSITO: Okay. With the organic acid salts, you were fine with all of them?

DR. LIEBLER: Correct.

DR. BELSITO: We're getting rid of the protein salts?


DR. BELSITO: For the organic substituted inorganic, we're getting rid of the dicetearyl phosphate, but leaving the other two?


DR. BELSITO: And we're getting rid of all the alkyl substituted ethanolamines?


DR. BELSITO: And then proceeding with the safe as used.

DR. LIEBLER: Yes.

DR. BELSITO: Okay. And then for the amides, that's page 25 of the book. The grouping, Dan, are you comfortable with the glycol ethers?

DR. LIEBLER: Sorry, I'm catching up to this. Okay.

MS. FIUME: You can see it at Panel Book 25, if that helps at all.

DR. LIEBLER: Report 25, I'm sorry. Okay. Yes. I'm okay with the glycol ethers.

DR. BELSITO: Okay. I'm going to try to MEA in the salts. There's a possible inhalation use now for ethanolamine. And we had previously said that it was not safe for aerosols, had we not? That was our prior conclusion? Page 34, CIR Panel Book 45, "Incidental Inhalation Spray," three reported uses or 3 percent concentration use, rather.

MS. FIUME: We previously said that it should only be in rinse-off products. And now it's used in the hair color spray, aerosol at 3 percent.



DR. BELSITO: Right.

MS. FIUME: Okay.

DR. BELSITO: We previously said it should be used only in rinse-off products.

MS. FIUME: Yes.

DR. BELSITO: So, do we have data to support its use at 3 percent in a spray?

MS. FIUME: And I don't know if this is applicable as to why it should not be used in a spray, but on page 11, Panel Book page 22, it has an effect on bronchial constriction.

SPEAKER: Yes.

DR. BELSITO: Right.

MS. FIUME: A 3.3 percent ethanolamine solution.

DR. BELSITO: Well, you know what, I think that we still have one more ingredient to go through. This was really more of an issue of deciding what goes into these reports, to open it and to add ingredients. So, I think we are opening it, we are splitting the reports, we have the MEA and salts that we're recommending with the MEA, amides, and glycol ethers that were please be aware when you're reading the report the next time that there's a reported leave-on use, which we previously did not comment on, and let's look at the data as we read it and see if it's worth it, and I would say close out MEA and MEA amides right now.

SPEAKER: Agreed.

DR. BELSITO: Okay.

MS. FIUME: Dr. Belsito, for the MEA, being that it's going to come back, do you want it insufficient data announcement for inhalation?

DR. BELSITO: No, quite honestly, I noted it. I didn't go back and look at the older report to see why we said rinse-off. Maybe it was simply because it was only used in rinse-off. I mean, did we have toxicity data to suggest it shouldn't be used in a leave-on?

I don't have any of that information available to me. I think, again, when we come back and look at it, I mean, I think at this hour, the panel is charged only to decide that, yes, we want to reopen it and these are the ingredients we want when we reopen it, and, by the way, there seems to be a new use, as well, which is another reason to reopen.

MARKS TEAM – ETHANOLAMINE – SEPT 2011

DR. MARKS: Good. Okay, next -- MEA. So there may be some -- this is the first time we've seen this report. It's a draft amended safety assessment of ethanolamine, which is the new name for mono ethanolamine.

So I guess the question is, are we going to change the cover of this to "Ethanolamine" in the next rendition, from "MEA." But it's historically good, because it's confusing, if we go from one to the other without having recognized that first. So, Monice, I appreciate that you put "MEA" on the front.

At any rate, in December we decided to reopen the '83 assessment of TEA, DEA and MEA. And, as you know, we decided to break these ingredients up, and now we have the MEA or, aka, the ethanolamine ingredients.

So I think the first thing we need to do is, on page 12, decide if we want to include -- so we have the inorganic salts, we have the organic acid salts, the protein salts, the organic-substituted, inorganic acid salts, and the alkyl-substitute ethanolamines. And, Ron, Tom, Ron, any either individuals or groups that you want to eliminate?



DR. HILL: I would like to see the alkyl-substituted ethanolamines removed.

DR. SHANK: I agree.

DR. SLAGA: I agree, too.

DR. HILL: And then unless we have direct data on that phosphate -- that was one that we removed on those others -- I'm not sure we need to keep it in here, either. Although, just a discussion point I'm tossing out there.

DR. MARKS: Actually, none of those alkyl-substituted ethanolamines are being used. So that's nice. So the one you talked -- this individual one, which is that again? Ron Hill?

DR. HILL: It would be the dicetearyl phosphate, but I'm --

DR. MARKS: Di -- oh, yes. Okay. So that's the organic-substituted inorganic acid salts. That's the last ingredient there. That's not being used, also. Ron -- that's not a reason to eliminate it. It's just do we keep it or not keep it?

DR. SHANK: It makes no difference to me.

DR. SLAGA: Yeah, I'd just leave it in.

DR. MARKS: Leave it in.

DR. HILL: I'm trying to find it in the structure table, because I thought I'd made --

MS. FIUME: Just so the Panel is aware, in DEA and TEA the phosphates were removed because there were no other phosphates that had been reviewed to date. Just so that you're aware.

DR. MARKS: So shall we remove it? With that -- being consistent?

DR. HILL: My concern with the dicetearyl phosphate was not just that it was phosphate, but that if you look at it, it looks a lot like a membrane phospholipid, but with saturated, rather than acyl lipid groups. And from a personal comfort level, without having some biological data on that -- even though I doubt there will be dermal penetration at all. It's just leave-on use -- it just seems scientifically inappropriate to keep it.

DR. MARKS: Okay.

DR. HILL: But that's just my opinion, for discussion.

DR. SHANK: That's good, because it's a no-brainer.

DR. MARKS: Yep. So we have --

DR. SHANK: If we have questions about it, we shouldn't have it.

DR. MARKS: So let me see. Now we need to go -- so, Monice broke this into two sections. If we go on page 25, we have the second section. Do we want to continue to have this as one report? And break it in -- this is more a, I guess initially, as a stylistic, do we want to -- in the past, we've actually taken it and broken things out. Do you want to keep the "Part II," these amides in? Or deal with them separately? Are there ones that you don't feel comfortable with? Or the whole group?

DR. SLAGA: Well, if we did it in the past with one of the others, I'd rather see it separated out.

DR. SHANK: I agree.

DR. SLAGA: To be consistent.

DR. SHANK: Yes -- well, and the chemistry. The amides have a different chemistry and a different conclusion -- at least on the leave-ons. I think it's logical to separate the amines from the amides.



DR. MARKS: Okay. So you would actually, if we were going to deal with these, have a totally separate report. Okay.

DR. HILL: And the other thing is, the main logic for keeping them combined is that somehow those amides were generating ethanolamine, and I'm not sure that we have data that indicates that.

DR. MARKS: Okay. So I think we've -- at least for this report, "Ethanolamine," or MEA, we're going to include in this report, on page 12, every ingredient -- starting from the bottom and working up -- every ingredient about MEA-laureth sulfate. Is that correct? Will it be included in this report?

DR. EISENMANN: So you've never reviewed silk.

DR. MARKS: Pardon?

DR. EISENMANN: There's a hydrolyzed silk one, and you've never reviewed silk. So -- at least I don't think -- Monice, has there ever been a review of silk?

MS. FIUME: I'm checking the table. No, we have not.

DR. MARKS: And we'll probably have little data, at least in this, because it's not an ingredient that's being used, the hydrolyzed silk. So -- is that a problem? Do you want to eliminate silk, since we haven't reviewed it?

DR. SHANK: Well, and the hydrolyzed collagen MEA is the only one in this group, of the ethanolamines, where there is a leave-on use. Or at least there's a concentration -- no reported use, but there's a concentration. Interesting how that happens. So maybe we should just eliminate both of the hydrolyzed proteins.

DR. HILL: My recollection was a statement was made-- I wasn't the one that made it -- was the thought that if the toxicology of a salt was primarily driven by the other component, that we will try not to review it along with the -- in this case it would the ethanolamine. That if we had toxicology it might be driven by the hydrolyzed silk component and not the ethanolamine.

DR. MARKS: Right. That's the add-on.

DR. HILL: And in that case, we would try to pare them out -- yeah.

DR. MARKS: So do you want to eliminate the protein salts the, also, Tom, and Ron Hill? To make it more straightforward?

DR. SHANK: Sure.

DR. MARKS: Okay. So let me restate that again. We will have -- I'll do it a little bit differently this time. The ingredients -- I didn't add it up -- the ingredients will be the inorganic acid salts, the organic acid salts, the organic-substituted inorganic acid salts, the lauryl sulfate and the laureth sulfate. And that would be the ingredients that would be reviewed in this report. And then we would separate out, in a separate report, the amides that are on page 25.

Okay. Is that -- we're okay with that? Now, let's move on to, then, with those ingredients on page 12. Are there any concerns, in terms of moving this forward. Do we have "insufficient data" needs? I like, Ron, that you eliminated the only leave-on, because there is some contradiction on sensitization. And also there is irritation with prolonged -- so it makes it simpler for me to feel comfortable about a rinse-off, that these are safe. Any other needs?

DR. SHANK: We're still on amines?

DR. MARKS: Yes. Yes, we're only on the amines. Should we discuss both? As separate? To me --

DR. SLAGA: I don't think we should.

DR. MARKS: No. I would just do the amines.

DR. SHANK: Okay.



DR. MARKS: What do you think, Tom? Ron?

DR. SLAGA: I agree.

DR. MARKS: And then bring the amides back in the future? What's -- what do you feel, Ron Shank? You obviously said, "are we only doing the one?" Or, actually, you're exactly right, it would be basically do we have enough information to feel that these ingredients are safe. We didn't actually go down the list of amides, but let's go back to the amines. We'll do that, and then you would bring out -- you would discuss, Tom, the amides at a totally separate setting.

DR. SLAGA: Yes.

DR. MARKS: Yes, I think time-wise, that makes sense.

DR. SHANK: Okay.

DR. MARKS: Okay.

DR. HILL: But I would have a lot of ingredients on that list that I thought should definitely come out.

DR. SLAGA: But we can make that --

DR. HILL: We could make that decision whenever we saw them again.

DR. MARKS: Right.

DR. HILL: So long as --

DR. MARKS: Just hearing that --

DR. HILL: -- so I don't have to figure it out all over again.

DR. MARKS: Just hearing that -- well, better save that one, then.

DR. HILL: Yeah.

DR. MARKS: Just hearing that, it makes me even more want to not delve into the amides. So, how about the amines? Any problems?

DR. SLAGA: "Safe when formulated to be non- irritating?"

DR. SHANK: Yes.

DR. MARKS: Yes.

DR. HILL: I agree.

MS. FIUME: Do you need the term, "rinse-off" in the conclusion? Or is it -- because they're only used in rinse-offs, it could be "safe as used, when formulated to be non-irritating."

DR. MARKS: I think -- remember, we always put the caveat "if not being used," so it would be in the same the use and the same concentration. So that means it's implied it's safe in only rinse- offs.

DR. HILL: However, it probably --

DR. MARKS: We can do that in the discussion.

DR. HILL: -- in many, if not all of these, might be safe in leave-ons. It's just --

DR. MARKS: Right.



DR. HILL: -- we'd have to see that.

DR. MARKS: So, "safe," "not-irritating." And then we would issue a tentative amended safety assessment. And this would only be for the amines on page 12. Any other comments? Okay. And we will, if it comes up -- I'm going to make that motion, and then I'll also, if it comes up, basically say we tabled the discussion on the amides, and recommend that be a separate report, done at a later date.

FULL PANEL – ETHANOLAMINE – SEPT 2011

Moving on to the next item, this is a green item, the MEA group, Dr. Marks?

DR. MARKS: This is the first time we've seen this split-out in which now we have the MEA group or what will be known, a/k/a, as the ethanolamine group. First when we looked at this we wanted to decide which actual add-on. This is an add-on. This would be an amended report so we're dealing with the rules that we set up for add-ons. If we go to Panel Book page 12, the add-ons from the 21 ingredients there we felt could be done easily, the inorganic acid salts and the organic acid salts. We had concerns about the proteins in the protein sales that we could easily deal with them, so we wanted those to be removed. And the organic substituted inorganic acid salts, we wanted the last one of those, the stearyl phosphate, the phosphate removed. Then all the ingredients in the alkyl substituted, ethanol removed so that we had a more limited list of ingredients that would be included. If we go to page 25 of the CIR Panel Book there was the second part of this report with the ethanolamides and we decided that we would separate this report out, table a discussion on these and not include it in this particular report since again we felt it would take more than just no-brainers to include those. So we would move then that the ingredients that I had mentioned on page 12, we would proceed forward, that they are safe as long as formulated to be nonirritating. That's a motion for a tentative amended safety assessment of the ethanol amines.

DR. BERGFELD: Dr. Belsito?

DR. BELSITO: I have a couple of issues. Believe it or not, we agree on the ingredients to be included in the ethanolamine report, but I would point out that previously we had said that these were safe for use only in rinse-off products. So now we have some leave-on uses and perhaps because we were doing this at the last report age 5:15, we took it upon ourselves to assume that what we're being asked us do we want to split the reports into MEA salts and MEA amides and we said, yes, two reports. The ethanolamine report ingredients as agreed upon just now. The ethanolamide report, we felt that all the ingredients listed there could be included in that report and that we would be going forward with two new reports, p.s., when you look at the ethanolamine realize that the last go-around we had said rinse-offs only, so do we have data to support leave-ons? And p.s., when we did some of the ethanolamides before, we were setting concentration limits I think because of irritation. I think the approach we've now used is that you can predict irritation, so when formulated to be nonirritating. But we wanted both reports reopened under separate categories, the ingredients in the ethanolamine report as listed, the ingredients in the ethanolamide report as listed on page 14 or 25 of the Panel Book, and that's all we are prepared to do today and not issue any safety assessments.

DR. BERGFELD: Jim?

DR. MARKS: That's fine. So essentially table it with the suggestions we've made.

DR. BELSITO: This is a new report, not tabling it, just agreeing on the ingredients to go forward.

DR. BERGFELD: I don't think we have to table.

DR. MARKS: Okay.

DR. BERGFELD: So it is a consensus agreement to separate this report into two group entities and to throw it back to CIF staff.

DR. BELSITO: Right.

DR. BERGFELD: Good. I see everyone shaking their heads so I'll assume that's a straw vote to move on so we will.



Rep

ort

Tentative Amended Safety Assessment

Ethanolamine and Ethanolamine Salts as Used in Cosmetics

December 13, 2011 All interested persons are provided 60 days from the above date to comment on this Tentative Amended Safety Assessment and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings, will be available at the CIR office for review by any interested party and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. F. Alan Andersen. The 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Monice M. Fiume, Senior Scientific Analyst/Writer, and Bart A. Heldreth, Ph.D. Chemist, CIR.

© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 "

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Table of Contents

Abstract ........................................................................................................................................................................................ 1 Introduction ................................................................................................................................................................................. 1 Chemistry ..................................................................................................................................................................................... 2

Method of Manufacture .......................................................................................................................................................... 2 Impurities ................................................................................................................................................................................ 2

Use ............................................................................................................................................................................................... 3 Cosmetic ................................................................................................................................................................................. 3 Non-Cosmetic ......................................................................................................................................................................... 3

Toxicokinetics.............................................................................................................................................................................. 3 In-Vitro ............................................................................................................................................................................... 4 Dermal ................................................................................................................................................................................ 4

Non-Human ................................................................................................................................................................... 4 Oral ..................................................................................................................................................................................... 5

Non-Human ................................................................................................................................................................... 5 Other ................................................................................................................................................................................... 5

Non-Human ................................................................................................................................................................... 5 Toxicological Studies .................................................................................................................................................................. 5

Acute (Single) Dose Toxicity ................................................................................................................................................. 5 Dermal ................................................................................................................................................................................ 5 Oral ..................................................................................................................................................................................... 6 Inhalation ............................................................................................................................................................................ 6 Other ................................................................................................................................................................................... 6

Repeated Dose Toxicity .......................................................................................................................................................... 6 Dermal ................................................................................................................................................................................ 6 Oral ..................................................................................................................................................................................... 6 Inhalation ............................................................................................................................................................................ 6

Reproductive and developmental Toxicity .................................................................................................................................. 7 Dermal ................................................................................................................................................................................ 7 Oral ..................................................................................................................................................................................... 7

Genotoxicity ................................................................................................................................................................................ 8 In Vitro .................................................................................................................................................................................... 8

Irritation and Sensitization ........................................................................................................................................................... 9 Dermal Irritation ..................................................................................................................................................................... 9

Non-Human ................................................................................................................................................................... 9 Human ........................................................................................................................................................................... 9

Sensitization ............................................................................................................................................................................ 9 Non-Human ................................................................................................................................................................... 9 Human ........................................................................................................................................................................... 9

Provocative Testing ............................................................................................................................................................ 9 Ocular Irritation .................................................................................................................................................................... 10

In Vitro ........................................................................................................................................................................ 10 Non-Human ................................................................................................................................................................. 10

Occupational ExpoSure ............................................................................................................................................................. 10 Occupational Exposure Limits .............................................................................................................................................. 10

Miscellaneous Studies ............................................................................................................................................................... 10 Effect on Hepatic Choline ..................................................................................................................................................... 10 Effect on Bronchoconstriction .............................................................................................................................................. 11

Summary .................................................................................................................................................................................... 11 Draft Discussion ........................................................................................................................................................................ 13 Draft Conclusion ........................................................................................................................................................................ 13 Tables......................................................................................................................................................................................... 14

Table 1. Definition and structures of ethanolamine and ethanolamine-containing ingredients .......................................... 14 Table 2. Conclusions of previously reviewed ingredients and components ........................................................................ 15 Table 3. Physical and chemical properties .......................................................................................................................... 16 Table 4a. Frequency and concentration of use according to duration and type of exposure ............................................... 16 Table 4b. Ingredients not reported to be in use .................................................................................................................... 17 Table 4c. Status for use in Europe according to the EC CosIng Database for ethanolamine ingredients ........................... 17

References ................................................................................................................................................................................. 18



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ABSTRACT

The CIR Expert Panel assessed the safety of ethanolamine and12 of its salts as used in cosmetics. Ethanolamine functions as a pH adjuster. The majority of the salts are reported to function as surfactants; the others are reported to function as a pH adjuster, hair fixative, or preservative. The Panel reviewed available animal and clinical data, as well as information from previous CIR reports. Since data were not available for each individual ingredient, and since the salts dissociate freely in water, the Panel extrapolated from previous reports to support safety. The Panel concluded that to be completed once a conclusion is reached

INTRODUCTION

In 1983, the Cosmetic Ingredient Review (CIR) Expert Panel issued a report on the safety of Triethanolamine,

Diethanolamine, and Monoethanolamine. In 2010, the Panel decided to reopen that safety assessment as three separate

reports and to include additional related ingredients in each of the new reviews. Both diethanolamine and triethanolamine

have been re-reviewed, with conclusions of safe in the present practices of use and concentration when formulated to be non-

irritating, and that these ingredients should not be used in cosmetic products in which N-nitroso compounds can be formed.1,2

The International Nomenclature Cosmetic Ingredient (INCI) name for monoethanolamine is now ethanolamine.

This assessment addresses ethanolamine and ethanolamine salts. The acid salt ingredients (as recited below) would be

expected to dissociate into ethanolamine and the corresponding acid, some of which have been reviewed separately. In most

cases, this means that the composition of these salts is stoichiometrically half ethanolamine (i.e. as its conjugate acid).

In 1983, the Expert Panel concluded that ethanolamine, an ingredient that functions in cosmetics as a pH adjuster, is

safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of

the skin, and ethanolamine should only be used in rinse-off products.3 In that review, it was shown that ethanolamine is a

skin and eye irritant in animals, and clinical studies with formulations containing ethanolamine indicated that it is a human

skin irritant. Also, there was indication that the longer ethanolamine was in contact with the skin, the greater the likelihood

of irritation.

The following 12 salts are included in the re-review of ethanolamine:

Inorganic Acid Salts Ethanolamine HCl MEA-Sulfite Organic Acid Salts MEA-Benzoate MEA-Salicylate MEA-Cocoate MEA-Tallowate MEA-Undecylenate MEA-Laureth-6 Carboxylate MEA PPG-6 Laureth-7 Carboxylate MEA-PPG-8-Steareth-7 Carboxylate Organic-Substituted Inorganic Acid Salts MEA-Lauryl Sulfate MEA-Laureth Sulfate

Ethanolamine HCl is reported to function as a pH adjuster and a buffering agent. MEA-sulfite is reported to function

as a hair fixative. The majority of the ethanolamine salts are reported to function as surfactants. However, MEA-benzoate

and MEA-salicylate are reported to function as preservatives, not surfactants.



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MEA-salicylate also has been reviewed previously by the CIR Expert Panel. In 2003, the Panel concluded that

MEA-salicylate is safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin’s

sun sensitivity, or, when increased sun sensitivity would be expected; directions for use include the daily use of sun

protection.4

The definitions and structures of ethanolamine and the ethanolamine-containing ingredients listed above are

provided in Table 1. Since the ingredients included in this review consist of ethanolamine and one or more components, and

the safety of some of these components has been reviewed by the CIR, the conclusions of those relevant ingredients that have

been previously reviewed are provided in Table 2.

CHEMISTRY

Ethanolamine is an amino alcohol. (Figure 1). Ethanolamine is produced commercially by aminating ethylene oxide with ammonia; the replacement of one hydrogen of ammonia with an ethanol group produces ethanolamine. Ethanolamine typically contains a small amount of diethanolamine (DEA).

Figure 1. Ethanolamine

Ethanolamine is reactive and bifunctional, combining the properties of alcohols and amines. At temperatures of 140°-160°C, ethanolamine will react with fatty acids to form ethanolamides. Additionally, the reaction of ethanolamines and sulfuric acid produces sulfates, and, under anhydrous conditions, ethanolamine may react with carbon dioxide to form carbamates. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine3

While many secondary amines and amides are readily nitrosated to form isolatable nitrosamines and nitrosamides,

primary amines, such as ethanolamine, ultimately yield diazonium salts instead of nitrosamines.5

Acid Salts The acid salts (inorganic acid salts, organic acid salts, and sulfate salts), named above, are ion pairs which freely

dissociate in water (e.g., Figure 2). Therefore, these salts are closely related to the corresponding free acids and

ethanolamine. In other words, MEA-undecylenate is comprised of undecylenic acid and ethanolamine.

Figure 2. MEA-Undecylenate

Physical and chemical properties are summarized in Table 3.

Method of Manufacture

Ethanolamine Ethanolamine is produced by reacting 1 mole of ethylene oxide with 1 mole of ammonia. Typically, ethylene oxide

is reacted with ammonia in a batch process to produce a crude mixture of approximately one-third each ethanolamine,

diethanolamine, and triethanolamine, which are then separated, achieving varying degrees of single component purity.6

Residual ethylene oxide is not expected.

Ethanolamine combines with long-chain fatty acids to produce neutral carboxylates, also called alkanolamine

soaps.7

Impurities

Ethanolamine contains a small amount of diethanolamine. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine3



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USE

Cosmetic

Ethanolamine and ethanolamine HCl are reported to function in cosmetics as pH adjusters; ethanolamine HCl is also

reported to function as a buffering agent.8 MEA-sulfite is reported to function as a hair fixative. The majority of the ethanol-

amine salts are reported to function as surfactants. However, MEA-benzoate and MEA-salicylate are reported to function as

preservatives, not surfactants.

Amines, such as ethanolamine, can be useful in pH adjustment because they can both donate a proton in an alkaline

environment and accept a proton in an acidic environment. For ethanolamine HCl, a proton has already been accepted from

HCl, but ethanolamine HCl can certainly function as a proton donor.

VCRP data obtained in 2011 report that ethanolamine is used in 788 formulations.9 All of the uses are in rinse-off

products (Don Havery, personal communication), and 772 uses are in hair coloring formulations.10 A few of the other

ethanolamine-containing ingredients are in use, but all of those are reported to be used in less than 15 rinse-off formulations.

According to data submitted by industry in response to a recent survey conducted by the Personal Care Products

Council (Council), ethanolamine is used in rinse-off products (only) at up to 18%.11 MEA-lauryl sulfate has the highest

reported concentration of use, with a concentration of 35% reported in rinse-off formulations. Use data for ethanolamine and

all other in-use ethanolamine-containing ingredients are provided in Table 4a. Ethanolamine ingredients not reported to be in

use, according to VCRP data and the Council survey, are listed in Table 4b.

Monoalkylamines, monoalkanolamines, and their salts are listed by the European Commission in Annex III Part 1:

the list of substances which cosmetic products must not contain, except subject to the restrictions and conditions laid down.12

These restrictions for these ingredients include an allowed maximum secondary amine content of 0.5% in finished product;

do not use with nitrosating agents; minimum purity of 99%; maximum secondary amine content of 0.5% for raw materials;

maximum nitrosamine content of 50 µg/kg; and must be kept in nitrite-free containers. The ingredients named in this report

that have these restrictions are listed in Table 4c.

Information provided by Health Canada indicates that ethanolamine is used primarily in hair coloring products, with

concentrations of use of ≤30% (Health Canada, personal communication). Ethanolamine is also reported to be used in

Canada at concentrations of ≤30% in non-coloring hair preparations and rinse-off formulations, and at ≤10% in leave-on

formulations; this includes reported use at 0.3-3% in baby products and 3-10% in lipsticks.

Non-Cosmetic

Ethanolamine is used in the manufacture of emulsifiers and dispersing agents for textile specialties, agricultural chemicals, waxes, mineral and vegetable oils, paraffin, polishes, cutting oils, petroleum demulsifiers, and cement additives. It is an intermediate for resins, plasticizers, and rubber chemicals. It is also used as a lubricant in the textile industry, as a humectant and softening agent for hides, as an alkalizing agent and surfactant in pharmaceuticals, as an absorbent for acid gases, and in organic syntheses. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Ethanolamine has uses as an indirect food additive; according to 21 CFR 175.105 ethanolamine is allowed for use as

a component of adhesives.13 Ethanolamine is also used as a rust inhibitor in water-based metalworking fluids.14

TOXICOKINETICS

Ethanolamine is the only naturally occurring ethanolamine in mammals; it occurs in phospholipids known as phosphatides. In an in vitro study, absorption of undiluted and aqueous (aq.) ethanolamine was much greater through mouse skin than it was through human, rat, or rabbit skin; human skin was the least permeable. The percentage of the dose that penetrated through mouse and human skin was greater with aq. ethanolamine compared to undiluted ethanolamine; 16.92% of the undiluted and 24.79% of the aq. ethanolamine absorbed through mouse skin while 0.61% undiluted and 1.11% aq. ethanolamine penetrated through human skin. In split-thickness pig skin, 5% of the dose of ethanolamine HCl in ethanol penetrated percutaneously. In a metabolism



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and distribution study, ethanolamine HCl was applied dermally to human skin-grafted and ungrafted athymic nude mice. Radioactivity was recovered in the skin (18.4% recovered in grafted skin; 12.1% in ungrafted skin), liver (~24-26%), and kidneys (~2%). Approximately 5% of the radioactivity was recovered in the urine; 10% of the radioactivity recovered in the urine was unchanged ethanolamine, and the major urinary metabolites were urea and glycine. In an oral study in Wistar rats fed a diet containing 100-1000 mg/kg ethanolamine HCl for 10 wks, plasma ethanolamine concentrations increased in a dose-dependent manner from <3 mg/kg in control animals and <4 mg/kg in low dose animals to 60-81 mg/kg in high-dose animals. Ethanolamine is the only naturally occurring ethanolamine in mammals, and it is excreted in the urine. Ethanolamine was converted to phosphatidylethanolamine (PE) in the liver, blood, and brain of female rats that were dosed intraperitoneally (i.p.) with radiolabeled ethanolamine. The step-wise methylation of PE that converts it to phosphatidylcholine (PC) did not occur in the brain. Labeled respiratory carbon dioxide has been found in rats after i.p. administration of labeled ethanolamine. A coenzyme-B12-dependent ethanolamine deaminase-mediated conversion of ethanolamine to acetaldehyle and ammonia was demonstrated. Intraperitoneal administration of ethanolamine to rats increased blood urea and blood glutamine, and the researchers suggested that ethanolamine was an ammonia source. Additional researchers, upon detection of labeled acetate in the urine of rats fed labeled ethanolamine, suggested that ethanolamine is phosphorylated by ATP in vivo, converted to acetaldehyde, ammonia, and inorganic phosphate, and the acetaldehyde is oxidized to acetate. The researchers further hypothesized that the removal of phosphorylated ethanolamine by its conversion to acetate may exert a regulatory effect on PE biosynthesis. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Ethanolamine.3

Ethanolamine occurs naturally in phospholipids known as phosphatides.7 Ethanolamine is a structural component of

the phospholipids as part of the headgroups in phospholipid bilayers. In man and other animals, the alcohol group of ethanol-

amine is phosphorylated, and phosphorylated ethanolamine is transferred to cytidine monophosphate to form cytidine-5’-di-

phosphoethanolamine and phospholipids via diacylglycerol.

In-Vitro

Ethanolamine Three full thickness skin preparations from CD rats, CD-1 mice, and New Zealand White rabbits and 6 samples

from female mammoplasty patients were used to compare the dermal penetration of ethanolamine through skin of different

species.15 [14C]Ethanolamine (98.8% purity; specific activity [sp. act.] 15.0 mCi/mmol) was applied to the skin sample

undiluted or as an aq. solution at a dose of 4 mg/cm2. Dose volumes of 7 µl undiluted [14C]ethanolamine or 32 µl of the aq.

solution (22% w/w) were applied to the exposed surface of the skin (1.77 cm2) for 6 h. With undiluted ethanolamine, the

percentage of the dose that penetrated the skin was 5.98, 16.92, 8.66, and 0.61% through rat, mouse, rabbit, and human skin,

respectively. With aq. ethanolamine, 1.32, 24.79, 1.87, and 1.11%, of the dose penetrated through rat, mouse, rabbit, and

human skin, respectively. In vitro absorption of undiluted and aq. ethanolamine was much greater through mouse skin than

human skin, and human skin was the least permeable of all the skin samples. With human skin samples, the cumulative dose

absorbed was greater with aq. ethanolamine as compared to undiluted ethanolamine. The researchers hypothesized that

enhanced penetration of aq. ethanolamine may be attributable to elevated skin hydration.

Ethanolamine HCl The dermal penetration of [1,2-14C]ethanolamine HCl was evaluated in vitro using split-thickness skin from wean-

ling Yorkshire pigs.16 An ethanolic solution was prepared so that a 5 µl application to 0.8 cm2 of skin gave a chemical dose

of 4 µg/cm2 and a radioactive dose of approximately 0.05 µCi. After 50 h, 11% of the dose was lost to evaporation, 5%

penetrated percutaneously, and 62% was recovered in the skin residue. Seven to nine times more radioactivity was recovered

in the upper 100 µm layer, compared to recovery from the remaining dermis.

Dermal

Non-Human The distribution and metabolism of ethanolamine was determined using groups of 5 male athymic nude mice with

human skin grafts and ungrafted athymic nude mice.16 [1,2-14C]Ethanolamine HCl in ethanol was applied at a dose of 4.0 µg



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(3.6 µCi) to a 1.45 cm2 area of grafted or non-grafted skin. Penetration appeared similar for both groups. Radioactivity in

expired carbon dioxide (CO2) appeared 30 min after dosing, and the amount recovered at 30 min was 0.76% for grafted skin

and 0.83% of the dose for ungrafted skin. After 24 h, 18.5-19% of the dose was recovered in expired CO2. Distribution was

also similar for both groups. At 24 h after dosing, 24.3-25.8% of the dose was recovered in the liver and 2.24-2.53% in the

kidneys. At the application site, 18.4% of the radioactivity was recovered in the grafted skin, and 12.1% was recovered in the

ungrafted skin. The amount of radioactivity recovered in the urine was 4.6 and 5.2% for grafted and ungrafted nude mice,

respectively. Unchanged ethanolamine comprised 10.2% of the urinary radioactivity. The major urinary metabolites were

urea and glycine, comprising 39.9 and 20.4% of the urinary radioactivity. Minor urinary metabolites were serine, uric acid,

choline, and unidentified ninhydrin-positive compounds.

The radioactivity in proteins and amino acids isolated from the liver, human skin grafts, and mouse skin was deter-

mined as an evaluation of the metabolism of ethanolamine. The researchers stated that the appearance of 14C in skin and

hepatic amino acids and proteins, and the incorporation of ethanolamine into phospholipids, was evidence of extensive

metabolism of the absorbed ethanolamine. The liver was the most active site of ethanolamine metabolism.

Oral

Non-Human In a dietary two-generation reproductive toxicity study (described later in the ‘Reproductive and Developmental

Toxicity’ section), blood samples were taken from groups of 10 male and 10 female F0 and F1 Wistar rats that were fed 0,

100, 300, or 1000 mg/kg ethanolamine HCl in feed for 10 wks.17 Plasma levels of ethanolamine, calculated as ethanolamine

HCl, increased in a dose-dependent manner. The plasma concentration of ethanolamine was <3 mg/kg for control male and

female F0 and F1 animals. In the low dose group, the plasma concentration values of ethanolamine were <4 mg/kg, in the

mid-dose animals, the levels were 8-11 mg/kg, and in the high dose animals, the plasma ethanolamine levels ranged from 60-

81 mg/kg.

Other

Non-Human Five male athymic nude mice were dosed intraperitoneally (i.p.) with 4.0 µg (3.6 µCi) of [1,2-14C]ethanolamine

HCl in ethanol, and the distribution and metabolism were examined following dosing.7 Radioactivity was detected in expired

CO2, increasing gradually over time. After 24 h, 18% of the radioactivity was detected in expired air.

TOXICOLOGICAL STUDIES

Single applications of 5 and 10% ethanolamine were mildly toxic to mouse skin. The dermal LD50 in rabbits was 1.0-2.5 g/kg ethanolamine. Oral LD50 values were 0.7-15.0 g/kg in mice and 1.0-2.9 g/kg in rabbits. The inhalation LC50 of a mixture containing ethanolamine, hydroxylamine, 1-aminopropanolo-2-ol, catechol, and water was estimated as 2.48 mg/l.

Acute (Single) Dose Toxicity

Dermal

Female C3H mice were used to determine the in vivo and in vitro morphological response of mouse skin exposed to

a single application of 1, 5, or 10% ethanolamine in acetone.18 In vivo, ethanolamine was applied to an area of skin 1 inch in

diameter, the animals were killed the next day, and the treated skin was removed and processed. In vitro, ethanolamine was

applied to a 1-inch diameter mouse skin disc for 1 min, and the skin discs were then cultured for 20 h. No lesions were ob-

served in vivo or in vitro at any concentration tested. Lactate dehydrogenase activity in the in vitro samples was statistically

significantly elevated with 5 and 10% ethanolamine, suggesting that ethanolamine was mildly toxic to the skin at these

concentrations.



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The dermal LD50 in rabbits was 1.0-2.5 g/kg ethanolamine.7

The acute dermal toxicity of a mixture containing ethanolamine (as well as hydroxylamine, diglycolamine,

propylene glycol, catechol, and water; percentages not specified) was determined by applying 2g/kg of the mixture to the

shaved backs of 5 male and 5 female rabbits.19 The dermal LD50 of the mixture was >greater than the 2 g/kg dose. In a

similar study with a formulation containing ethanolamine (and hydroxylamine, diglycolamine, gallic acid, and water;

percentages not specified), the LD50 of the mixture in rabbits was 1.24 g/kg bw.20

Oral

The acute oral toxicity of ethanolamine, concentration not specified, ranged from 1.72-2.75 g/kg for rats. Using 90-120 rats, 20% aq. ethanolamine had an LD50 of 2.14-2.74 g/kg, based on results of studies performed over a 10 yr time period. With groups of 10 rats, a hair preparation containing 5.9% ethanolamine had an LD50 of 14.1 g/kg when diluted and 12.9 ml/kg when undiluted. In a study using guinea pigs, all in the group of 2 or 3 guinea pigs survived oral dosing with 0.6 g/kg ethanolamine, while none survived dosing with 7.0 g/kg. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

In oral studies, the LD50 of ethanolamine was 0.7-15.0 g/kg in mice and 1.0-2.9 g/kg in rabbits.7

The acute oral toxicity of a mixture containing ethanolamine (as well as hydroxylamine, diglycolamine, propylene

glycol, catechol, glycolic acid and water; percentages not specified) was determined using groups of 5 male and 5 female

rats.21 The oral LD50 of the mixture was 0.95 g/kg. In a similar study with a formulation containing ethanolamine (and

hydroxylamine, diglycolamine, gallic acid, and water; percent in formulation not specified), the oral LD50 of the mixture was

0.815 g/kg bw.

Inhalation

The acute inhalation toxicity of a mixture containing ethanolamine (as well as hydroxylamine, 1-amino-propano-2-

ol, catechol, and water; percent of each not specified) was determined using groups of 5 male and 5 female rats. The animals

were exposed to 1.11, 1.61, 2.13, or 2.84 mg/l for 4 h. All animals exposed to 2.84 mg/l died. All animals in the other test

groups survived. The inhalation LC50 of the mixture was estimated to be 2.48 mg/l.21

Other

The intraperitoneal LD50 of ethanolamine was 1.05 g/kg for mice. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Repeated Dose Toxicity

Dermal

Percutaneous application of 4 mg/kg/day ethanolamine to rats resulted in nonspecific histological changes in the heart and lung, fatty degeneration of the liver parenchyma, and subsequent focal liver necrosis. The duration of dosing was not specified. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Oral

Groups of 10 rats were fed 0-2.67 g/kg/day ethanolamine for 90 days. Heavy livers and kidneys were observed at ≥0.64 g/kg/day, and deaths and “major pathology” occurred with ≥1.25 g/kg/day. In a 2-yr dietary study in which groups of 12 beagle dogs were fed 0-0.0975 g/kg/day of a hair dye composite that contained 22% ethanolamine, no toxic effects were observed. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Inhalation

The dominant effects of “continuous exposure” of dogs, guinea pigs, and rats to 5-6 ppm ethanolamine vapor were skin irritation and lethargy. No dogs or rodents exposed to 12-26 ppm ethanolamine vapor for 90 days died, but mortality was reported in dogs exposed to 102 ppm ethanolamine vapor for 2 days and rodents exposed to 66-75 ppm ethanolamine vapor for 24-28 days. Dogs and rodents exposed to 66-102 ppm ethanolamine vapor had behavioral changes, pulmonary and hepatic inflammation, hepatic and renal damage, and hematological changes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3



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REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Dermal developmental toxicity studies were performed using rats and rabbits. In a study in which gravid rats were dosed with 10-225 mg/kg bw/day ethanolamine on days 6-15 of gestation, the no-observed effect level (NOEL) was 75 mg/kg/day for maternal toxicity and 225 mg/kg/day for embryonal/fetal toxicity. In rabbits that were dosed dermally with 10-75 mg/kg bw/day ethanolamine on days 6-18 of gestation, the NOEL was 10 mg/kg bw/day for maternal toxicity and 75 mg/kg bw/day for embryonal/fetal toxicity. Significant skin irritation was observed in the high dose groups for both rats and rabbits. In a Chernoff-Kavlock post-natal mouse screening assay, oral dosing with 850 mg/kg/day ethanolamine on days 6-15 of gestation resulted in 16% mortality of maternal mice and a reduced number of viable litters. In a study in which Wistar rats were gavaged with 40-450 mg/kg bw/day aq. ethanolamine on days 6-15 of gestation, the NOEL was 120 mg/kg/day for maternal toxicity and 450 mg/kg/day for developmental toxicity. In an oral study in which Long-Evans rats were dosed with 50-500 mg/kg aq. ethanolamine on days 6-15 of gestation, there was no significant maternal toxicity, but embryolethality was increased in the 500 mg/kg group and more reproductive and developmental effects were observed involving male pups compared to female pups. There was an increase in malformed pups in all dose groups. In a dietary two-generation study in rats with 100-1000 mg/kg bw/day ethanolamine HCl, the no-observed adverse effect level (NOAEL) was 300 mg/kg bw/day for systemic toxicity and for reproductive effects, and the NOAEL was 1000 mg/kg bw/day for developmental toxicity.

Dermal

The developmental toxicity of dermally-applied aq. ethanolamine was evaluated using groups of 30-45 gravid

Sprague-Dawley rats and 15 gravid New Zealand White rabbits.22 Ethanolamine was applied at doses of 0, 10, 25, 75, and

225 mg/kg bw/day to the backs of rats on days 6-15 of gestation, with a dose volume of 1 ml/kg. Significant skin irritation,

consisting of erythema followed by necrosis, scabs, and scar formation, occurred with 225 mg/kg ethanolamine, but not at the

other dose levels. No effects on kidney or liver weights were reported. Despite maternal effects in the 225 mg/kg dose

group, no effects on reproductive parameters were observed at any dose, and there were no treatment-related increases in the

visceral or skeletal malformations. In rats, the no-observed effect level (NOEL) was 75 mg/kg/day for maternal toxicity and

225 mg/kg/day for embryonal/fetal toxicity.

In rabbits, 0, 10, 25, and 75 mg/kg bw/day ethanolamine was applied to the back (2 ml/kg) on days 6-18 of gesta-

tion. Severe skin irritation at the application site, consisting of necrosis, exfoliation, and crusting, was observed in the 75

mg/kg group, and crusting, transient erythema, and edema were observed in a few rabbits of the 25 mg/kg dose group. No

effects on kidney or liver weights were reported. As with the rats, no effects on reproductive parameters were observed at

any dose, and there were no treatment-related increases in the visceral or skeletal malformations. In rabbits, the NOEL was

10 mg/kg bw/day for maternal toxicity. No effect on embryonal/fetal toxicity was observed at the highest dose level of 75

mg/kg bw/day.

Oral

Ethanolamine No reproductive or developmental effects were observed in groups of gravid rats given a hair dye and base containing 22% ethanolamine in the diet at concentrations ≤7800 ppm on days 6-15 of gestation. No differences in reproductive or developmental parameters were observed when male rats were fed treated diet for 8 wks prior to and during mating with undosed females or when female rats were fed treated feed for 8 wks prior to dosing until day 21 of lactation. These females were mated with undosed males. Additionally, no teratologic effects were induced by dosing gravid rabbits with ≤19.5 mg/kg/day of the hair dye and base by gavage on days 6-18 of gestation. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Ethanolamine.3

The teratogenic potential of ethanolamine was evaluated in a Chernoff-Kavlock postnatal mouse screening assay.23

Gravid CD-1 mice were dosed orally with 850 mg/kg/day ethanolamine on days 6-15 of gestation, resulting in 16% mortality

of maternal mice and reduced numbers of viable litters. Litter size, percentage survival of pups, birth weight, and pup weight

gains were not affected.



8

A preliminary study was performed in which gravid Wistar rats were dosed orally with 0-500 mg/kg/day aq. etha-

nolamine; details not provided.24 Maternal effects were observed in the high dose animals, but no embryonal/fetal effects

were observed at any dose. Based on these results, groups of 40 Wistar rats were dosed by gavage with 0, 40, 120, or 450

mg/kg bw/day aq. ethanolamine on days 6-15 of gestation. On day 20 of gestation, 25 dams/group were killed and necrop-

sied, while the remaining 15 were allowed to litter, and then killed on day 21 of lactation. Despite evidence of maternal toxi-

city in the 450 mg/kg group, as indicated by statistically significant decreases in maternal body weights and feed consump-

tion, no effects on reproductive parameters, incidences of visceral or skeletal malformations, or postnatal growth were ob-

served at any dose. The NOEL for maternal toxicity was 120 mg/kg/day. No effect on developmental toxicity was observed

at the highest dose level of 450 mg/kg/day.

Groups of 10 gravid Long-Evans rats were dosed by gavage with 50, 300, or 500 mg/kg aq. ethanolamine on days 6-

15 of gestation, and a negative control group of 34 gravid rats was dosed with water only.25 The animals were killed and

examined on day 20 of gestation. Significant maternal toxicity was not noted. Embryolethality was significantly increased in

the 500 mg/kg group, and male pups were affected more than female pups. Male pups were also more severely affected than

female pups at all dose levels in regards to intrauterine growth retardation and increased gross structural anomalies that were

considered indicative of depressed fetal growth. However, pups of either sex who were contiguous to male siblings were

more adversely affected that those contiguous to one or more female siblings. Male pups contiguous to male siblings (mMm)

were, apparently, resorbed (mRm). The number of malformed pups per dam was significantly increased in animals dosed

with 300 mg/kg ethanolamine. The number of malformed pups, when evaluated as a percent of the litter affected, was signifi-

cantly increased for all 3 dose groups.

Ethanolamine HCl Groups of 25 male and 25 female Wistar rats (F0 parental generation) were fed 0, 100, 300, or 1000 mg/kg bw/d

ethanolamine HCl for at least 75 days prior to mating.17 Twenty-five male and 25 female F1 pups/group were continued on

the test diets of their parents, and then mated, becoming the F1 parental generation. The study was terminated after the

weaning of the F2 pups. No test substance-related adverse reproductive, developmental, or toxic effects were observed in any

of the pups or parental animals of the 100 or 300 mg/kg bw/d groups. In the 1000 mg/kg group, adverse effects on fertility

and reproduction were evidenced by statistically significant decreases in absolute and relative weights of the epididymides

and cauda epididymidis in male F0 and F1 parents and statistically significant decreased number of implantation sites,

increased post-implantation loss, and smaller litters in female F0 and F1 parents. Sperm head count in the cauda epididymidis

and absolute and relative liver weights were also statistically significantly decreased in male F0 parents. Body weight gains

of both the F0 and F1 parental animals were statistically significantly decreased during gestation when compared to controls,

as was feed consumption during lactation. There were no test-related signs of developmental toxicity observed in F1 and F2

pups of this dose group. The NOAEL was 300 mg/kg bw/day for systemic toxicity and for reproductive effects. No effect on

developmental toxicity was observed at the highest dose level of 1000 mg/kg/day.

GENOTOXICITY

In Vitro

Ethanolamine, with and without metabolic activation using liver preparations from rats induced with a polychlorinated biphenyl mixture, was not mutagenic to Salmonella typhimurium TA100 or TA1535. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Ethanolamine was negative in most Ames tests at concentrations ≤2000 μg/plate;26,27 however “weak mutagenic

effects” were reported in one study.28 Ethanolamine, 25-500 µg/ml, was negative in a cell transformation assay using

hamster embryo cells.29 Ethanolamine was clearly cytotoxic at 500 µg/ml. Ethanolamine did not produce chromosomal



9

aberrations in rat liver cells,26 but a “weak positive” response was reported in human lymphocytes.28 (Concentrations tested

were not provided.)

IRRITATION AND SENSITIZATION

Ethanolamine HCl, ≤70%, did not have a sensitizing effect in a local lymph node assay. In a maximization studying guinea pigs with intradermal and epicutaneous inductions of 0.6 and 10.3% aq. ethanolamine, respectively, positive reactions were observed at challenge. Possible cross-reactions to 5% triethanolamine and 7% diethanolamine were reported. In provocative testing of metalworkers with dermatitis, a higher reaction to ethanolamine was observed for the patients as compared to control subjects. In a study of hairdressers and clients, cosensitization to diethanolamine was reported for 38% of the patients that reacted to ethanolamine. Ethanolamine, tested at 0.05, 0.5, and 1%, was classified as a moderate irritant in the in vitro rabbit corneal epithelial model evaluating ocular irritation potential.

Dermal Irritation

Non-Human Ethanolamine was corrosive to rabbit skin with single semi-occlusive patches of 30, 85 and 100% on intact and abraded skin. When applied to rabbit ears using non-occlusive applications and to shaved skin of the abdomen under semi-occlusive patches, ≥10% was corrosive, >1% was extremely irritating, and 1% was irritating. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Human In a study in which a formulation containing 5.9% ethanolamine was applied to the backs of 12 female subjects for 23 h/day for 21 days, the formulation was considered an experimental cumulative irritant. Results observed during the induction phase of a patch test of 165 subjects using a formulation containing 11.47% ethanolamine were interpreted by the Expert Panel as irritation. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Sensitization

Non-Human A local lymph node assay was performed to evaluate the sensitization potential of ethanolamine (as the hydro-

chloride salt).14,30 Groups of 6 female CBA/Ca mice were treated on the ear with 10, 40, or 70% w/w aq. ethanolamine HCl.

Ethanolamine HCl did not have a skin sensitizing effect.

In a maximization study using 15 Dunkin-Hartley guinea pigs, intradermal and epicutaneous inductions with 0.6%

and 10.3% aq. ethanolamine, respectively, were performed after 10% sodium lauryl sulfate pre-treatment.14 (Ethanolamine

contained less than 0.1% diethanolamine and triethanolamine.) At challenge with 0.41, 2.05, or 4.1% ethanolamine, 3, 2, and

3 animals, respectively, reacted positively after 3 days. Two of the 15 test animals reacted to the vehicle, but none of the con-

trol animals reacted to ethanolamine or the vehicle. Possible cross-reactions to 5% triethanolamine occurred in 3 animals,

and to 7% diethanolamine in 2 animals. In a second test using the same protocol, no animals reacted to 0.41% ethanolamine,

2 reacted to 2.05% ethanolamine, and 1 reacted to 4.1% ethanolamine. Additionally, 1 animal reacted to 10% triethanol-

amine and 2 reacted to 7% diethanolamine. The control animals did not react to any of the ethanolamines.

Human A formulation containing 5.9% ethanolamine, tested undiluted, and one containing 11.47% ethanolamine, tested at 5% in 25% alcohol, were not sensitizing in clinical studies. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

Provocative Testing

Metalworkers that were dermatitis patients were patch tested with 2% ethanolamine in petrolatum (pet.).31 The

patches were applied for 1-2 days. On day 3, 3 of 155 patients (1.9%) had positive reactions.

Patch testing was performed with 2% ethanolamine in pet. in 199 patients with suspected metalworking fluid contact

dermatitis.32 (All patients were metalworkers.) Patches were applied for 1 or 2 days. On day 3, 40 patients had positive

reactions, 16 (?), 19 (+), 4 (++), and 1 (+++). The % positive reactions was 11.6%.



10

A patch test using 2% ethanolamine in pet. was performed on 370 patients with suspected dermatitis to ethanol-

amine-containing metal-working fluids and on 452 control subjects.33 A 10-fold higher reaction was seen in the patient

group, with 12.2% of the patients having positive reactions, as compared to 1.3% in the control group.

Over a 3-yr period, 11/595 hairdresser clients (1.9%) and 7/401 female hairdressers (1.8%) reacted positively to 2%

ethanolamine in pet.14 In 22 patients with suspected intolerance to oxidative hair dye components, 4 had a positive reaction

to 2% ethanolamine in pet. Over a 15-yr period, provocative patch testing using ethanolamine was performed on 9602 sub-

jects. There were 363 positive reactions (3.8%) to ethanolamine, and most of the reactions (277; 2.9%) were weak positives.

There were 55 irritant reactions (0.6%) reported. Cosensitization was reported; 38% of the patients that reacted to ethanol-

amine also tested positive with diethanolamine. Occupational sensitization was reported; of 5884 male patients evaluated,

2.9% that did not work in the metal industry had positive reactions to ethanolamine, as opposed to 7.0% of those working in

the metal industry and 15.2% of those exposed to water-based metalworking fluids.

Ocular Irritation

In Vitro Ethanolamine

The ocular irritation potential of ethanolamine was evaluated in vitro in the rabbit corneal epithelium model.34 At

concentrations of 0.05, 0.5, and 1%; ethanolamine was classified as a moderate ocular irritant in this assay.

Non-Human Using 6 rabbits, 30% aq. ethanolamine was moderately irritating to rabbit eyes. Undiluted ethanolamine, instilled as a volume of 0.005 ml, produced severe injury to rabbit eyes. A hair preparation containing 5.96% ethanolamine had a maximum avg. irritation score of 0.7/110 for rinsed and unrinsed eyes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

OCCUPATIONAL EXPOSURE

Ethanolamine inhalation by humans has been reported to cause immediate allergic responses of dyspnea and asthma and clinical symptoms of acute liver damage and chronic hepatitis. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.3

A case of occupational asthma in an industrial worker exposed to a detergent containing 8% ethanolamine was

reported.35 Since the detergent was used in hot water, release of ethanolamine vapor was greater than if the detergent temper-

ature was lower. Exposure to vapors from ethanolamine in cleaning solutions can irritate the nose, throat, and lungs.36

Occupational Exposure Limits

The Occupational Safety and Health Administration permissible exposure level for ethanolamine is 3 ppm (6

mg/m3) as an 8-hr time-weighted average concentration.37 The National Institute for Occupational Health and Safety has a

recommended exposure limit of 3 ppm (8 mg/m3) for a 10 h workday and 40 h work week; the short-term exposure limit is 6

ppm (15 mg/m3), for periods not to exceed 15 min.38

MISCELLANEOUS STUDIES

Effect on Hepatic Choline

The effects of ethanolamine HCl on hepatic choline was determined in the F0 and F1 parental rats from the two-

generation feeding study described earlier in this report.39 Liver weights were determined for all parental rats at necropsy,

and the livers of control and high-dose animals (1000 mg/kg bw/day) were examined microscopically. Feeding ethanolamine

HCl to rats did not affect liver weights of any of the animals. No adverse microscopic affects in the livers of high-dose rats

were reported. Liver samples of F1 female rats of the test and control groups were analyzed for choline, phosphocholine,

glycerophosphocholine, and phosphatidylcholine. A statistically significant increase in phosphocholine and phosphatidyl-

choline was observed in the 100 and 300 mg/kg bw/day dose groups, but no other statistically significant difference in



11

choline content were reported. In that there was no dose-response, these effects were not considered dose-related. The

researchers concluded that “based on the combined hepatic observations, ethanolamine hydrochloride does not affect hepatic

choline metabolism in the rat.”

Effect on Bronchoconstriction

The effect of ethanolamine on bronchoconstriction was investigated using a group of 4 anesthetized male Hartley

guinea pigs.40 When an aerosol of 0.1 ml/kg of 3.3% ethanolamine solution was inhaled through a tracheal cannula, broncho-

constriction was observed. The results were compared to those obtained using an aerosol of potassium hydroxide. Broncho-

constriction induced by ethanolamine was greater than that induced by potassium hydroxide. Additional testing suggested

that ethanolamine-induced bronchoconstriction may not result from induction of acetylcholine or histamine release, but that it

may result partly from an agonistic effect of ethanolamine at the histamine-H1 receptor and the muscarinic receptor.

SUMMARY

This report assesses the safety of ethanolamine and salts as used in cosmetics. The ethanolamine salts are expected

to dissociate into ethanolamine and the corresponding acid. Ethanolamine typically contains a small amount of diethanol-

amine as an impurity. (Diethanolamine has been found to be safe in the present practices of use and concentration when

formulated to be non-irritating; it should not be used in cosmetic products in which N-nitroso compounds can be formed).

Ethanolamine and ethanolamine HCl function in cosmetic formulations as a pH adjuster. The organic salts and the organic-

substituted inorganic salts mostly function as surfactants, with the exception of MEA-benzoate and MEA-salicylate, which

are preservatives. MEA-sulfite is reported to function as a hair fixative.

In 2011, ethanolamine was reported to be used in 788 formulations, 772 of which are hair coloring formulations.

Of the ethanolamine-containing ingredients that are in use, none have more than 15 uses. Reported maximum use concentra-

tions of ethanolamine are 0.0002-18%. MEA-lauryl sulfate has the highest reported maximum use concentration at 35% in

rinse-off formulations. In Europe, monoalkylamines, monoalkanolamines, and their salts are on the list of substances which

must not form part of the composition of cosmetic products, except subject to restrictions and conditions laid down. These

restrictions include a maximum secondary amines contaminant content of 0.5% in finished products, a maximum secondary

amines content of 0.5% in raw materials, and a maximum nitrosamine content of 50 µg/kg.

Ethanolamine is the only naturally occurring ethanolamine in mammals; it occurs in phospholipids known as phos-

phatides. In an in vitro study, absorption of undiluted and aq. ethanolamine was much greater through mouse skin than it was

through human, rat, or rabbit skin; human skin was the least permeable. The percentage of the dose that penetrated through

mouse and human skin was greater with aq. ethanolamine compared to undiluted ethanolamine; 16.92% of the undiluted and

24.79% of the aq. ethanolamine absorbed through mouse skin while 0.61% undiluted and 1.11% aq. ethanolamine penetrated

through human skin. In split-thickness pig skin, 5% of the dose of ethanolamine HCl in ethanol penetrated percutaneously.

In a metabolism and distribution study, ethanolamine HCl was applied dermally to human skin-grafted and ungrafted athymic

nude mice. Radioactivity was recovered in the skin (18.4% recovered in grafted skin; 12.1% in ungrafted skin), liver (~24-

26%), and kidneys (~2%). Approximately 5% of the radioactivity was recovered in the urine; 10% of the radioactivity recov-

ered in the urine was unchanged ethanolamine, and the major urinary metabolites were urea and glycine. In an oral study in

which Wistar rats were fed a diet containing 100-1000 mg/kg ethanolamine HCl for 10 wks, plasma ethanolamine concentra-

tions increased in a dose-dependent manner from <3 mg/kg in control animals and <4 mg/kg in low dose animals to 60-81

mg/kg in high-dose animals.

Single applications of 5 and 10% ethanolamine were mildly toxic to mouse skin. The dermal LD50 in rabbits was

1.0-2.5 g/kg ethanolamine. Oral LD50 values were 0.7-15.0 g/kg in mice and 1.0-2.9 g/kg in rabbits. The 4 h inhalation LC50



12

of a mixture containing ethanolamine, hydroxylamine, 1-aminopropanolo-2-ol, catechol, and water was estimated as 2.48

mg/l. Percutaneous application of 4 mg/kg/day ethanolamine to rats for an unspecified length of time resulted in nonspecific

histological changes in the heart and lung, fatty degeneration of the liver parenchyma, and subsequent focal liver necrosis. In

a dietary study in which rats were fed 0-2.67 g/kg/day ethanolamine for 90 days, heavy livers and kidneys were observed at

≥0.64 g/kg/day, and deaths and “major pathology” occurred with ≥1.25 g/kg/day. In a 2-yr dietary study in which beagle

dogs were fed 0-0.0975 g/kg/day of a hair dye composite that contained 22% ethanolamine, no toxic effects were observed.

In repeated-dose inhalation studies, the dominant effects of “continuous exposure” of dogs, guinea pigs, and rats to 5-6 ppm

ethanolamine vapor were skin irritation and lethargy; mortality was observed in dogs exposed to 102 ppm ethanolamine

vapor for 2 days and in some rodents exposed to 66-75 ppm ethanolamine vapor for 24-28 days. Dogs and rodents exposed to

66-102 ppm ethanolamine vapor had pulmonary and hepatic inflammation, hepatic and renal damage, and hematological

changes.

Dermal developmental toxicity studies were performed using rats and rabbits. In a study in which gravid rats were

dosed with 10-225 mg/kg bw/day ethanolamine on days 6-15 of gestation, the no-observed effect level (NOEL) was 75 mg/

kg/day for maternal toxicity and 225 mg/kg/day for embryonal/fetal toxicity. In rabbits that were dosed dermally with 10-75

mg/kg bw/day ethanolamine on days 6-18 of gestation, the NOEL was 10 mg/kg bw/day for maternal toxicity and 75 mg/kg

bw/day for embryonal/fetal toxicity. Significant skin irritation was observed in the high dose groups for both rats and rabbits.

In a Chernoff-Kavlock post-natal mouse screening assay, oral dosing with 850 mg/kg/day ethanolamine on days 6-15 of ges-

tation resulted in 16% mortality of maternal mice and a reduced number of viable litters. In a study in which Wistar rats were

gavaged with 40-450 mg/kg bw/day aq. ethanolamine on days 6-15 of gestation, the NOEL was 120 mg/kg/day for maternal

toxicity and 450 mg/kg/day for developmental toxicity. In an oral study in which Long-Evans rats were dosed with 50-500

mg/kg aq. ethanolamine on days 6-15 of gestation, there was no significant maternal toxicity, but embryolethality was in-

creased in the 500 mg/kg group and more reproductive and developmental effects were observed involving male pups com-

pared to female pups. There was an increase in malformed pups in all dose groups. In a dietary two-generation study in rats

with 100-1000 mg/kg bw/day ethanolamine HCl, the NOAEL was 300 mg/kg bw/day for systemic toxicity and for reproduc-

tive effects, and the NOAEL was 1000 mg/kg bw/day for developmental toxicity. The effect of ethanolamine HCl on hepatic

choline was investigated in the F0 and F1 parental rats, and it was concluded that ethanolamine HCl did not affect the hepatic

choline metabolism in the rat.

Ethanolamine was mostly negative in Ames tests (≤2000 μg/plate). Ethanolamine (≤500 μg/ml) was negative in a

cell transformation assay. Ethanolamine did not produce chromosomal aberrations in rat liver cells, but did produce a “weak

positive” response in human lymphocytes.

In non-human studies, semi-occlusive application of 30-100% ethanolamine was corrosive to rabbit skin. Irritation

responses ranging from irritating to corrosive were observed with 1-10% ethanolamine, respectively, applied non-occlusively

to rabbit ears and under semi-occlusive patches to rabbit skin. The degree of irritation increased with the concentration ap-

plied. In human studies, a formulation containing 5.9% ethanolamine was a cumulative irritant in a 21-day study, and an irri-

tant response was reported during the induction phase of a patch test of a formulation containing 11.47% ethanolamine.

Ethanolamine HCl, ≤70%, did not have a sensitizing effect in a local lymph node assay. In a maximization study in guinea

pigs with intradermal and epicutaneous inductions of 0.6 and 10.3% aq. ethanolamine, respectively, positive reactions were

observed at challenge. Possible cross-reactions to 5% triethanolamine and 7% diethanolamine were reported. In provocative

testing of metalworkers with dermatitis, a higher reaction to ethanolamine was observed for the patients as compared to con-

trol subjects. In a study of hairdressers and clients, cosensitization to diethanolamine was reported for 38% of the patients



13

that reacted to ethanolamine. In ocular irritation studies in rabbits, 30% aq. ethanolamine was moderately irritating to rabbit

eyes, and undiluted ethanolamine produced severe injury. A hair preparation containing 5.96% ethanolamine had a maxi-

mum average irritation score of 0.7/110 in rinsed and unrinsed eyes. Ethanolamine, tested at 0.05, 0.5, and 1%, was

classified as a moderate irritant in the in vitro rabbit corneal epithelial model evaluating ocular irritation potential.

One-tenth ml/kg of a 3.3% ethanolamine aerosol solution induced bronchoconstriction in guinea pigs. Ethanol-

amine-induced bronchoconstriction may result partly from an agonistic effect of ethanolamine at the histamine-H1 receptor

and the muscarinic receptor.

DRAFT DISCUSSION

The discussion for the report will be developed at the meeting. Some of the following discussion items might be

included.

While the Panel noted gaps in the available safety data for the ethanolamine-containing ingredients included in this

group, the Panel relied on the information available for ethanolamine in conjunction with previous safety assessments of the

components of ingredients. Those data could be extrapolated to support the safety of these ingredients. For example, coco-

nut acid has been found safe as used, and the Panel was able to extrapolate these data to support the safety of MEA-cocoate

(i.e., the ethanolamine salt of coconut acid).

The potential exists for dermal irritation with the use of products formulated using ethanolamine or ethanolamine

salts. The Expert Panel specified that products containing these ingredients must be formulated to be non-irritating.

The Panel was concerned with levels of free diethanolamine that could be present as an impurity in ethanolamine or

ethanolamine-containing ingredients. The Panel stated that the amount of free diethanolamine available must be limited to

the present practices of use and concentration of diethanolamine itself.

DRAFT CONCLUSION

The CIR Expert Panel concluded that ethanolamine and the 12 related ethanolamine salts, listed below, are safe in

the present practices of use and concentration described in this safety assessment when formulated to be non-irritating. Were

the ingredients not in current use (as indicated by *) to be used in the future, the expectation is that they would be used in

product categories and at concentrations comparable to others in this group.

Ethanolamine Ethanolamine HCl* MEA-Benzoate* MEA Cocoate MEA-Laureth-6 Carboxylate* MEA-Laureth Sulfate MEA-Lauryl Sulfate MEA-PPG Laureth-6 Carboxylate* MEA-PPG-8 Steareth-7 Carboxylate* MEA-Salicylate* MEA-Sulfite* MEA-Tallowate MEA-Undecylenate*



14

TABLES

Table 1. Definition and structures of ethanolamine and ethanolamine-containing ingredients Ingredient/ CAS No. Definition Reported Function8 Structure Ethanolamine 141-43-5

a primary amine with one ethanol functional group.

pH adjuster

Ethanolamine HCl 2002-24-6

the ethanolamine salt of hydrochloric acid.

pH adjuster; buffering agent

MEA-Sulfite 13427-63-9

the ethanolamine salt of hydrogen sulfite.

hair fixative

HONH3

HSO3

Organic Acid Salts MEA-Benzoate 4337-66-0 33545-23-2

the ethanolamine salt of benzoic acid.

preservative

MEA-Salicylate 59866-70-5

the ethanolamine salt of salicylic acid.

preservative

MEA-Cocoate 66071-80-5

the ethanolamine salt of coconut acid.

surfactant – cleansing agent; surfactant – foam booster

MEA-Tallowate

the ethanolamine salt of tallow acid.

IN VCRP; not in INCI Dictionary

MEA-Undecylenate 56532-40-2

ethanolamine salt of undecylenic acid

surfactant – cleansing agent

MEA-Laureth-6 Carboxylate

the ethanolamine salt of laureth-6 carboxylic acid (wherein “-6” represents the number ethylene glycol units, including the carboxylate).


MEA PPG-6 Laureth-7 Carboxylate

the ethanolamine salt of PPG-6 laureth-7 carboxylic acid (wherein “-7” represents the number ethylene glycol units, including the carboxylate).


HONH3

OO

OO

OO

OO

OO

CH3

CH3

CH3

O

CH3

O

CH3

O

CH3

CH3O

O



15

Table 1. Definition and structures of ethanolamine and ethanolamine-containing ingredients Ingredient/ CAS No. Definition Reported Function8 Structure MEA-PPG-8-Steareth-7 Carboxylate

the ethanolamine salt of PPG-8 steareth-7 carboxylic acid (wherein “-7” represents the number ethylene glycol units, including the carboxylate).


HONH3

OO O O O O O O OCH3

CH3O

CH3

O

CH3O

CH3

O O O

CH3

CH3

CH3

CH3O

O

Organic-Substituted Inorganic Salts MEA-Lauryl Sulfate 4722-98-9

is the ethanolamine salt of sulfated lauryl alcohol.


MEA-Laureth Sulfate 68184-04-3

the ethanolamine salt of sulfated, ethoxylated lauryl alcohol (wherein the number of ethylene glycol units ranges from 1 to 4).


Table 2. Conclusions of previously reviewed ingredients and components

Ingredient Conclusion

PREVIOUSLY REVIEWED INGREDIENTS

Ethanolamine is safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin, and MEA should only be used in rinse-off products (1983)3

MEA-Salicylate safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin’s sun sensitivity, or, when increased sun sensitivity would be expected; directions for use include the daily use of sun protection (2003)4

COMPONENTS

Ammonium Lauryl Sulfate Sodium Lauryl Sulfate

safe in formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin; in products intended for prolonged contact with skin, concentrations should not exceed 1% (1983)41

Benzoic Acid safe as used (2011)42

Coconut Acid safe as used (2008)43

Laureths safe as used when formulated to be non-irritating (2010)44

PPG safe as used when formulated to be non-irritating (2010)45

Sodium Laureth Sulfate and re-lated salts of ethoxylated alcohols

safe as used when formulated to be non-irritating (2010)46

Steareths safe as used when formulated to be non-irritating (2010)44



16

Table 3. Physical and chemical properties

Property Value Reference Ethanolamine

Physical Form clear viscous liquid 3 Color colorless 3 Odor ammonia-like 3 Molecular Weight 61.08 3 Specific Gravity 1.0117 (25°C) 3 Viscosity 18.95 (25°C) 3 Refractive Index 1.4542 (20°C) 7 Vapor Pressure 0.48 mm Hg (20°C) 3 pKa 9.5 (25°C0 7 Melting Point 10.3-10.5°C 3 Boiling Point 171°C 3 Water Solubility miscible with water 22 Other Solubility miscible with methanol and acetone

soluble in alcohol, ethanol, chloroform, glycerol, logroin

22 7

log Pow (estimated) -1.31 47 MEA Benzoate

Molecular Weight 165.19 (calculated) 48 pKa 8.0 g/cm3 ( (most basic; 25°C) (calculated) 48 Density 1.119 g/cm3 (20°C) (calculated) 48 Boiling Point 271.8°C (calculated) 48 log P 1.336 (25°C) (calculated) 48

Table 4a. Frequency and concentration of use according to duration and type of exposure

# of Uses10 Max. Concs. of Use (%)11 # of Uses9

Max. Concs. of Use (%)11

# of Uses9 Max. Concs. of Use

(%)11

Ethanolamine MEA Cocoate MEA-Laureth Sulfate

Totals* 788 0.0002-18 4 NR 13 NR

Duration of Use

Leave-On NR NR NR NR NR NR

Rinse-Off 788 0.0002-18 4 NR 13 NR

Diluted for (Bath) Use NR NR NR NR NR NR

Exposure Type

Eye Area NR NR NR NR NR NR

Incidental Ingestion NR NR NR NR NR NR

Incidental Inhalation-Spray NR 3 NR NR NR NR

Incidental Inhalation-Powder NR NR NR NR NR NR

Dermal Contact 3 0.0002-11 4 NR NR NR

Deodorant (underarm) NR NR NR NR NR NR

Hair - Non-Coloring 13 0.05-6 NR NR 1 NR

Hair-Coloring 772 3-18 NR NR 12 NR

Nail NR NR NR NR NR NR

Mucous Membrane 2 0.02-0.05 4 NR NR NR

Baby Products NR NR NR NR NR NR



17

Table 4a. Frequency and concentration of use according to duration and type of exposure

# of Uses9 Max. Concs. of Use (%)11 # of Uses9

Max. Concs of Use (%)11

MEA-Lauryl Sulfate MEA-Tallowate

Totals* 5 5-35 6 NR Duration of Use Leave-On NR NR NR NR

Rinse Off 5 5-35 6 NR

Diluted for (Bath) Use NR NR NR NR

Exposure Type

Eye Area NR NR NR NR

Incidental Ingestion NR NR NR NR

Incidental Inhalation-Spray NR NR NR NR

Incidental Inhalation-Powder NR NR NR NR

Dermal Contact 1 NR 6 NR

Deodorant (underarm) NR NR NR NR

Hair - Non-Coloring 4 5 NR NR

Hair-Coloring NR 35 NR NR

Nail NR NR NR NR

Mucous Membrane NR NR 6 NR

Baby Products 1 NR NR NR * Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses. NR – no reported uses Table 4b. Ingredients not reported to be in use Ethanolamine HCl MEA-Benzoate MEA-Laureth-6 –Carboxylate MEA-PPG-6 Laureth-7 Carboxylate

MEA-PPG-8 Steareth-7 Carboxylate MEA-Salicylate MEA-Sulfite MEA Undecylenate

Table 4c. Status for use in Europe according to the EC CosIng Database for ethanolamine ingredients Fatty Acid Monoalkylamines, monoalkanolamines, and their salts – listed in Annex III – restrictions12 (maximum secondary amine content of 0.5% in the finished product; do not use with nitrosating systems; minimum purity – 99%; maximum secondary amine content of 0.5% for raw materials; maximum nitrosamine content of 50 µg/kg; keep in nitrite free containers) Ethanolamine Ethanolamine HCl MEA PPG-6 Laureth-7 Carboxylate MEA-Benzoate MEA-Cocoate MEA -Laureth Sulfate

MEA -Laureth-6 Carboxylate MEA -Lauryl Sulfate MEA -PPG-8-Steareth-7 Carboxylate MEA -Salicylate MEA -Sulfite MEA –Undecylenate



18

REFERENCES

1. Fiume MM. Final Amended Report on the Safety Assessment of Diethanolamine and Its Salts as Used in Cosmetics. 2011. Available from the Cosmetic Ingredient Review, 1101 17th Street, NW, Suite 412, Washington, DC 20036. www.cir-safety.org.

2. Fiume MM. Final Amended Report on the Safety Assessment of Triethanolamine and Its Salts as Used in Cosmetics. 2011. Available from the Cosmetic Ingredient Review, 1101 17th Street, NW, Suite 412, Washington, DC 20036. www.cir-safety.org.

3. Elder RE (ed). Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. J Am Coll Toxicol. 1983;2:(7).

4. Andersen FA (ed). Safety assessment of salicylic acid, butyloctyl salicylate, calcium salicylate, C12-15 alkyl salicylate, capryloyl salicylic acid, hexyldodecyl salicylate, isocetyl salicylate, isodecyl salicyalte, magnesium salicylate, MEA-salicylate, ethylhexyl salicylate, potassium salicylate, methyl salicylate, myristyl salicylate, sodium salicylate, TEA-salicylate, and tridecyl salicylate. Int J Toxicol. 2003;22:(Suppl 3):1-108.

5. Rostkowska K, Zwierz K, Rózanski A, Moniuszko-Jakoniuk J, and Roszczenko A. Formation and metabolism of nitrosamines. Polish Journal of Environmental Studies. 1998;7:(6):321-325.

6. Dow Chemical Company. The alkanolamines handbook. 1988. Midland, MI: The Dow Chemical Company.Secondary reference in Knaak et al. 1997.

7. Knaak JB, Leung H-W, Stott WT, Busch J, and Bilsky J. Toxicology of mono-, di-, and triethanolamine. Review of Environmental Contamination and Toxicology. 1997;149:1-86.

8. Gottschalck T.E. and Bailey, J. E. eds. International Cosmetic Ingredient Dictionary and Handbook. Washington, DC: Personal Care Products Council, 2010.

9. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database. 2011. Washington, DC: FDA.Updated Feb 25.

10. Food and Drug Administration. Frequency of use of cosmetic ingredients. 2011. Submitted to CIR by Don Havery, FDA, on October 18, 2011.

11. Personal Care Products Council. 7-5-2011. Concentration of Use by FDA Product Category: Ethanolamine, Diethanolamine and Triethanolamine. Unpublished data submitted by Personal Care Products Council.

12. European Commission. European Commission Enterprise and Industry. Cosmetics - Cosing. Annex III/Part 1, 61 - Monoalkylamines, nomoalkanolamines and their salts. http://ec.europa.eu/consumers/cosmetics/cosing/index.cfm?fuseaction=search.details&id=33796. 2010. Date Accessed 10-5-2010.

13. Food and Drug Administration. Everything Added to Food in the United States (EAFUS). http://www.fda.gov/Food/FoodIngredientsPackaging/ucm115326.htm. 5-27-0010. Date Accessed 6-8-2010.

14. Lessmann H, Uter W, Schnuch A, and Geier J. Skin sensitizing properties of ethanolamines mono-, di-, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK) and review of literature. Contact Derm. 2009;60:243-255.

15. Sun JD, Beskitt JL, Tallant MJ, and Frantz SW. In vitro skin penetration of monoethanolamine and diethanolamine using excised skin from rats, mice, rabbits, and humans. J Toxicol -- Cut & Ocular Toxicol. 1996;15:(2):131-146.

16. Klain GC, Reifenrath WG, and Black KE. Distribution and metabolism of topically applied ethanolamine. Fund Appl Toxicol. 1985;5:S127-S133.

17. BASF. Ethanolamine hydrochloride. Two-generation reproduction toxicity study in Wistar rats - administration via diet. 2009. Report No. 75R0372/05055. Unpublished data submitted by the American Chemistry Council. June 2011. (106 pp).

18. Helman, R. G., Hall, J. W., and Kao, J. Y. Acute dermal toxicity: in vivo and in vitro comparisons in mice. Fundamental and Applied Toxicology. 1986;7:(1):94-100.

19. Anonymous. Letter to the Environmental Protection Agency reporting an actue dermal toxcity study of a formulation containing DEA. 6-7-2010. 8EHQ-10-17970.

20. Anonymous. Letter to the Environmental Protection Agency reporting actue dermal and oral toxcity studies of a formulation containing DEA. 6-9-2010. 8EHQ-0610-17985.



19

21. Anonymous. Letter to the Environmental Protection Agency reporting an actue inhalaton toxcity studies of a formulation containing DEA. 6-8-2010. 8EHQ-0610-17981A.

22. Liberacki AB, Neeper-Bradley TL, Breslin WJ, and Zielke GJ. Evaluation of developmental toxicity of dermally applied monoethanolamine in rats and rabbits. Fund Appl Toxicol. 1996;31:117-123.

23. Pereira M, Barnwell P, and Bailes W. Screening of priority chemicals for reproductive hazards, monoethanolamine, diethanolamine, , triethanolamine. NIOSH Contract No. 200-84-2735. Environmental Health Research and Testing, Inc. REport No. ETOX-85-1002. 1987.

24. Hellwig J and Liberacki AB. Short communication. Evaluation of the pre-, peri-, and postnatal toxicity of monothanolamine in rats following repeated oral adminstration during organogenesis. Fund Appl Toxicol. 1997;40:158-162.

25. Mankes RF. Studies on the embryopathic effects of ethanolamine in Long-Evans rats: Preferential embryopathy in pups contiguous with male siblings in utero. Teratog.Carcinog Mutagen. 1986;6:403-417.

26. Dean BJ, Brooks TM, Hodson-Walker G, and Hutson DH. Genetic toxicology testing of 41 industrial chemicals. Mutat Res. 1985;153:57-77.

27. Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, and Zeiger E. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen. 1986;8:(Suppl 7):1-119.

28. Arutyunyan RM, Zalinyan RM, Mugnetsyan EG, and Gukasyan LA. Mutagenic action of latex polumerization stabilizers in different test systems. Tsitol Genet. 1987. 21: pp.450-456. Secondary referenc ein Knaak et al. 1997.

29. Inoue K, Sunakawa T, Okamoto K, and Tanaka Y. Mutagenicity tests and in vitro transformation assays on triethanolamine. Mutat Res. 1982;101:305-313.

30. BASF. Ethanolamine hydrochloride Murine Local Lymph Node Assay (LLNA). 2007. Unpublished data sumitted by the American Chemistry Council on October 8, 2010. (44 pages).

31. Geier, J, Lessmann H, Frosch, PJ., Koch, Patrick, Aschoff, R, Richter, G, Becker, D, Eckert, C, Uter, Wg, Schnuch, A, and Fuchs, T. Patch testing with components of water-based metalworking fluids. Contact Dermatitis. 2003;49:(2):85-90.

32. Geier, J, Lessmann, H, Dickel, H, Frosch, PJ., Koch, P, Becker, D, Jappe, U, Aberer, W, Schnuch, A, and Uter, W. Patch test results with the metalworking fluid series of the German Contact Dermatitis Research Group (DKG). Contact Dermatitis. 2004;51:(3):118-130.

33. Geier J, Lessmann H, Schnuch A, and Uter W. Diagnostic quality of patch test preparation monoethanolamine 2% pet. Contact Derm. 2005;52:171-173.

34. Matsuda S, Hidama M, Shibayama H, Itou N, and Iwaki M. Application of the reconstructed rabbit corneal epithelium model to assess the in vitro eye irritancy test of chemicals. Yakugaku Zasshi. 2009;129:(9):1113-1120.

35. Savonius B, Keskinen H, Tupperainen M, and Kanerva L. Occupational asthma caused by ethanolamines. Allergy. 1994;49:877-881.

36. Bello A, Quinn MM, Perry MJ, and Milton DK. Characterization of occupational exposures to cleaning products used for common cleaning tasks - A pilot study of hospital cleaners. Envron Health. 2009;8:11.

37. Occupational Safety and Health Administration (OSHA). Occupational safety and health guideline for ethanolamine. http://www.osha.gov/dts/chemicalsampling/data/CH_239000.html. 1996. Date Accessed 2-8-2011.

38. National Institure for Occupational Safety and Health (NIOSH). NIOSH Pocket guide to chemical hazards: ethanolamine. http://www.cdc.gov/niosh/npg/npgd0256.html. 11-18-2010.

39. Dow Chemical Company. Hepatic choline levels in rats after repeated dose feeding of ethanolamine hydrocholoride. 2009. Unpublished data submitted by the American Chemistry Council, June 2011. (15 pp).

40. Kamijo, Y., Hayashi, I., Ide, A., Yoshimura, K., Soma, K., and Majima, M. Effects of inhaled monoethanolamine on bronchoconstriction. Journal of Applied Toxicology. 2009;29:(1):15-19.

41. Elder RL (ed). Final report on the safety assessment of sodium lauryl sulfate and ammonium lauryl sulfate. J Am Coll Toxicol. 1983;2:(7):127-181.



20

42. Johnson WJ, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Amended Final Safety Assessment of Benzyl Alcohol mand Benzoic Acid and its Salts and Benzyl Ester. 9-26-2011. Available from CIR, 1101 17th ST, NW, Ste 412, Washington, DC 203; [email protected]. http://cir-safety.org/newreports.shtml

43. Diamante C, Bergfeld WF, Belsito DV, Klaassen CD, Hill RA, Liebler DC, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Amended Safety Assessment of Cocos Nucifera (Coconut) Oil, Coconut Acid, Hydrogenated Coconut Acid, Hydrogenated Coconut Oil, Ammonium Cocomonoglyceride Sulfate, Butylene Glycol Cocoate, Caprylic/Capric/Coco Glycerides, Cocoglycerides, Coconut Alcohol, Coconut Oil Decyl Esters, Decyl Cocoate, Ethylhexyl Cocoate, Hydrogenated Coco-Glycerides, Isodecyl Cocoate, Lauryl Cocoate, Magnesium Cocoate, Methyl Cocoate, Octyldodecyl Cocoate, Pentaerythrityl Cocoate, Potassium Cocoate, Potassium Hydrogenated Cocoate, Sodium Cocoate, Sodium Cocomonoglyceride Sulfate, Sodium Hydrogenated Cocoate, and Tridecyl Cocoate. 2008. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.

44. Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Klaassen CD, Liebler DC, Hill RA, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. CIR Expert Panel final amended report on alkyl PEG ethers as used in cosmetics. 2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.

45. Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks A, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final amended report of the Cosmetic Ingredient Review Expert Panel. Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics. 2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.

46. Robinson VC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the amended safety assessment of sodium laureth sulfate and related salts of sulfated ethoxylated alcohols. Int J Toxicol. 2010;29:(Supple 3):151S-161S.

47. Inchem. Ethanolamine. http://www.inchem.org/documents/icsc/icsc/eics0152.htm. 2004. Date Accessed 2-8-2011.

48. ACD/Labs. Advanced Chemistry Development (ACD/Labs) Software. 2011. (9.02):



JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY Volume 2, Number 7, 1983 Mary Ann Liebert, Inc., Publishers

8

Final Report on the Safety Assessment of

Triethanolamine, Diethanolamine, and Monoethanolamine

Triethanolamine (TEA), Diethanolamine (DEA), and Monoethanolamine (MEA) are amino alcohols used in cosmetic formulations as emulsifiers, thickeners, wetting agents, detergents, and alkalizing agents. The nitrosation of the ethanolamines may result in the formation of N-nitrosodiethanolamine (NDELA) which is carcinogenic in laboratory animals.

In single-dose oral toxicity for rats, TEA was practically nontoxic to slightly toxic, and DEA and MEA were slightly toxic. long-term oral ingestion of the ethanolamines by rats and guinea pigs produced lesions limited mainly to the liver and kidney. long-term cutaneous applications to animals of the ethanolamines also produced evidence of hepatic and renal damage. TEA and DEA showed little potential for rabbit skin irritation in acute and subchronic skin irritation tests. MEA was corrosive to rabbit skin at a 30% concentration in a single semioccluded patch application and at a > 10% concentration in 10 open applications over a period of 14 days.

The ethanolamines were nonmutagenic in the Ames test and TEA is also nonmutagenic to Bacillus subtilis. TEA did not cause DNA-damage inducible repair in an unscheduled DNA synthesis test. TEA had no carcinogenic or cocarcinogenic activity when dermally applied to mice for 18 months.

Clinical skin testing of TEA and cosmetic products containing TEA and DEA showed mild skin irritation in concentrations above 5%. There was very little skin sensitization. There was no phototoxicity or photosensitization reactions with products containing up to 20.04% TEA. A formulation containing 11.47% MEA and a formulation containing 1.6% DEA and 5.9% MEA were irritating to human skin in patch tests.

The Panel concludes that TEA, DEA, and MEA are safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of ethanolamines should not exceed 5%. MEA should be used only in rinse-off products, TEA and DEA should not be used in products containing N-nitrosating agents.

183



184 COSMETIC INGREDIENT .REVIEW

CHEMICAL AND PHYSICAL PROPERTIES

Structure

T riethanolamine (CAS No. 102-71-6) (TEA), Diethanolamine (CAS No. 11 l-42-2) (DEA), and Monoethanolamine (CAS No. 141-43-5) (MEA) are amino alco-

hols. They are produced by aminating ethylene oxide with ammonia. The replacement with ethanol groups of three, two, or one hydrogen of ammonia results in TEA, DEA, or MEA, respectively. The chemical formulas of the ethanolamines are as follows:

Triethanolamine N

Diethanolamine H-N/CH2C"20"

'C"2CH20"

H Monoethanolamine k

H' -CH2CH20"

Properties

TEA, DEA, and MEA are clear, colorless, viscous liquids with ammoniacal odors. They are hygroscopic and are strong bases. The ethanolamines are soluble in water, alcohol, and chloroform, and are insoluble in benzene, ether, and petroleum distillates. (l-61 Chemical and physical properties of TEA, DEA, and MEA are presented in Table 1. A sampling of the variety of values available in the literature is given for several chemical and physical properties. This variation may reflect the use of different grades of chemicals.

Reactivity

TEA, DEA, and MEA are reactive and are bifunctional, combining the properties of alcohols and amines. The ethanolamines will react at room temperature with fatty acids to form ethanolamine soaps, and DEA and MEA will react at temperatures between 140° and 160°C with fatty acids to form ethanolamides. The reaction of ethanolamine and sulfuric acid produces sulfates, and DEA and MEA may react, under anhydrous conditions, with carbon dioxide to form carbamates.‘1-3)

The ethanolamines can act as antioxidants in the autoxidation of fats of both animal and vegetable origin. TEA and DEA have stronger antioxidant effects than MEA (I) TEA is an antioxidant as measured by the Tetrahymena photodynamic assay. (8)

TEA and DEA can react with nitrite or oxides of nitrogen to form N-nitrosodiethanolamine (NDELA). As yet, MEA has not been found to form a stable nitrosamine.‘9,10’ MEA can react with an aldehyde to form DEA, and then can be



ASSESSMENT: TEA, DEA, AND MEA 185

TABLE 1. Chemical and Physical Properties.

Property TEA DEA MEA Ref.

149.19 105.14 61.08 6

1.1242

1 .0179

1 .0117

1.0881

1.0919

1.092

1.0985

1.1255

1.124

1.126

1.0693

0.9998

0.9844

3,s 6

6

2

5

6

6

1

4

5

1013

590.5 18.95

65.7

380

351.9

53.85 5.03

24

360

335.4

277-279

335,

decomposes

17.9

20-21.2

21.2

21.57

decomposes

268.8

268.0

171 l-3

170.8 6

172.2 4

170.5 5

28.0 10.3 l-3

28.0 10.5 4

28.0 10.5 5

28.0 10.3 6

534 660 825 l-3

<O.Ol

0.01 0.01

0.48 5

0.4 l-3

1.4852

10.5

1.4747

1.4753

11.0

1.4544

1.4539

12.05

Molecular weight

Specific gravity

2014 T

20120 T

2514 “C

3014 “C

30/20 T

30120 T

4014 T

6014 “C

not specified

not specified

not specified

Viscosity fcps)

2OT

25’C

30 “C

30 “C

6OT

not specified

Boiling Point (“C)

760 mm Hg

760 mm Hg

not specified

not specified

Melting Point FC)

Heat of Vaporization (joules/g)

760 mm Hg

Vapor Pressure (mm H@

2OT

not specified

Refractive Index

20 T

2OT

30 oc

30 T

pH of a 0.1 N aqueous solution

nitrosated to form NDELA.(9) The optimum pH for nitrosamine formation is variously reported to be between 1 and 6, and the reaction rate decreases as the pH increases. (9-12) Neutral solutions require 100,000 times as much nitrite as strong acid solutions in order to form the same amount of nitrosamine.(‘“*‘2) However, in the presence of catalysts such as chloral or an aldehyde, nitrosation reactions may occur up to a pH of 11. (9) The rate of NDELA formation in the pH range 4-9 is four to six times greater in the presence of formaldehyde than in its absence.(13) Higher temperatures and longer reactions times increase the yield of



186 COSMETIC INGREDIENT REVIEW

nitrosamine.‘“) Nitrosation reactions and salt formation reactions compete in aqueous solutions. (lo) The nitrosation by nitrites of DEA in an oil-in-water e’mul- sion to NDELA can be inhibited by ascorbic acid or sodium bisulfite or much less effectively inhibited by potassium sorbate incorporated into the aqueous phase or can be inhibited by ascorbyl palmitate incorporated into the oil phase.(14)

Methods of Manufacture and Impurities

The ethanolamines are commercially produced by aminating ethylene oxide with ammonia. The reaction temperature can be adjusted to produce mostly TEA or MEA.(‘-‘,“) The product is purified by distillation. A “low freeze grade” product can be prepared by adding up to 15% water.(1-3)

TEA contains small amounts of DEA and MEA, and DEA contains small amounts of TEA and MEA. MEA contains a small amount of DEA.(‘-‘s’~) TEA used in cosmetics may contain a maximum of 0.5% water, 0.05% sulfated ash, and 15 ppm iron.“‘)

Analytical Methods

Qualitative and quantitative determinations of the ethanolamines are made by calorimetric procedures, (16,18-21) titrimetric methods,(16s20,22-28) thin-layer chromatography,(29-32) gas chromatography,(23-25.33-39) gravimetric analysis,(39) thermogravimetric analysis,(40) the Kjeldahl method, and the Van Slyke procedure.(41) Positive identification of the ethanolamines can be made by comparison with published infrared spectra. (39042*43) UV absorbance spectra are available for TEA and MEA.(44)

Jones et al.(33) used gas chromatography to determine the amount of TEA in a simulated vanishing cream and shampoo. They did a preliminary separation into classes of compounds and were then able to recover between 96% and 101% of the TEA added to the cosmetic formulations.

USE

Purpose in Cosmetics

Ethanolamine soaps, formed from the reaction at room temperature of TEA, DEA, or MEA and fatty acids, and ethanolamides, formed from the reaction at elevated temperatures of DEA and MEA and fatty acids, are used in cosmetic formulations as emulsifiers, thickeners, wetting agents, detergents, and alkalizing agents.(1-3*45)

Scope and Extent of Use in Cosmetics

Product types and the number of product formulations containing TEA, DEA, or MEA reported voluntarily to the Food and Drug Administration (FDA) in 1981 are presented in Table 2. Table 2 does not include products containing TEA- lauryl sulfate or TEA-coca-hydrolyzed animal protein. These two ingredients have been reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel in



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Skin

c

lea

nsin

g

pre

pa

ratio

ns

(co

ld c

rea

ms,

lo

tions

, liq

uid

s,

an

d p

ad

s)

De

pila

torie

s

Fac

e,

bo

dy,

a

nd

ha

nd

ski

n

ca

re

pre

pa

ratio

ns

(exc

lud

ing

sha

vin

g

pre

pa

ratio

ns)

Foo

t p

ow

de

rs

an

d s

pra

ys

Ho

rmo

ne

skin

c

are

pre

pa

ratio

ns

Mo

istu

rizin

g

skin

-ca

re

pre

pa

ratio

ns

Nig

ht

skin

c

are

pre

pa

ratio

ns

Past

e

ma

sks

(mud

p

ac

ks)

Skin

lig

hte

ners

Skin

fr

esh

ene

rs

Wrin

kle

sm

oo

the

rs

(re

mo

vers

)

Oth

er

skin

c

are

pre

pa

ratio

ns

Sunt

an

ge

ls,

cre

am

s,

an

d l

iqu

ids

Ind

oo

r ta

nnin

g

pre

pa

ratio

ns

Oth

er

sunt

an

pre

pa

ratio

ns

114

64

-

29

11

680

214

32

1

- - -

403 1 3

2 a3

2 17

10

- -

-

747

388

219

aa

171

19

44

5

260

19

38

7

349

69

164

47

15

3

28

10

- - -

- - - 1

-

1981

TO

TALS

27

57

2 2

a 20

40

90

8 16

50

127



TAB

LE

2.

(Co

ntin

ue

d.)

Tota

l no

. o

f To

tal

no.

NO

. p

rod

uct

form

ula

tions

w

ithin

e

ac

h c

onc

ent

ratio

n ra

nge

(%

)

form

ula

tions

c

ont

ain

ing

U

nre

po

rte

d

Pro

duc

t c

ate

go

ry

in c

ate

go

ry

ing

red

ient

c

onc

ent

ratio

n >5

0 >2

5-50

>l

O-2

5 >5

-10

>l-5

>o

. I-l

10

.1

Die

tha

no

lam

ine

Bub

ble

b

ath

s 47

5 4

- -

- -

- -

- 4

Perm

ane

nt

wa

ves

474

1 -

- -

- -

1 -

- H

air

dye

s a

nd

co

lors

(a

ll ty

pe

s

req

uiri

ng

c

aut

ion

sta

tem

ent

an

d p

atc

h te

st)

ail

12

- -

- -

12

- -

Na

il b

ase

co

ats

a

nd

und

erc

oa

ts

44

1 -

- -

1 -

-

1981

TO

TALS

la

-

- -

14

- 4

Mo

no

eth

an

ola

min

e

Ma

sca

ra

397

1 -

- -

- 1

-

Ha

ir c

on

diti

on

ers

47

8 2

- -

- -

- -

2 -

Ha

ir st

raig

hte

ners

64

2

- -

- -

2 -

-

Perm

ane

nt

wa

ves

474

13

- -

- -

2 9

2 -

Ha

ir d

yes

an

d c

olo

rs

(all

typ

es

req

uiri

ng

c

aut

ion

sta

tem

ent

an

d p

atc

h te

st)

a11

25

-

- -

- 9

7 9

-

Ha

ir sh

am

po

os

(co

lorin

g)

16

1 -

- -

- -

- 1

-

Ha

ir b

lea

ch

es

111

2 -

- -

- -

2 -

-

Oth

er

pe

rso

na

l c

lea

nlin

ess

pro

duc

ts

227

3 -

- -

2 -

1 Sh

avi

ng

c

rea

m

(ae

roso

l,

bru

shle

ss,

an

d l

ath

er)

11

4 1

- -

- -

- 1

- M

oist

uriz

ing

sk

in

ca

re

pre

pa

ratio

ns

747

1 -

- -

- -

1 -

1981

TO

TALS

51

-

- -

- 11

22

17

1

Da

ta f

rom

Re

f. 48

.




other documents.(46.47) Voluntary filing of product formulation data by cosmetic manufacturers, packagers, and distributors conforms to the prescribed format of preset concentration ranges and product types as described in the Code of Federal Regulations (21 CFR, Part 720.4). Some cosmetic ingredients are supplied by the manufacturer at less than 100% concentration and, therefore, the value reported by the cosmetic formulator or manufacturer may not necessarily reflect the actual concentration of the finished product; the concentration in such a case would be a fraction of that reported to the FDA. The fact that data are submitted only within the framework of preset concentration ranges also provides the op- portunity for overestimation of the actual concentration of an ingredient in a particular product. An entry at the lowest end of a concentration range is considered the same as one entered at the highest end of that range, thus introducing the possibility of a two- to lo-fold error in the assumed ingredient concentration.

In 1981, TEA, DEA, and MEA were reported to be ingredients of 2757, 18, and 51 cosmetic products, respectively. The majority of these products contained TEA, DEA, or MEA in a concentration of less than or equal to 5°/0.‘4s)

Surfaces to Which Commonly Applied

Cosmetic products containing ethanolamines may be applied to or come in contact with skin, eyes, hair, nails, mucous membranes, and respiratory epithelium. Small amounts may be ingested from lipstick (Table 2).14*l

Frequency and Duration of Application

Product formulations containing ethanolamines may be applied as many as several times a day and may remain in contact with the skin for variable periods of time following each application. Daily or occasional use may extend over many years (Table 2).(48)

Potential Interactions with Other Cosmetic Ingredients

N-nitrosating agents, present as intentional ingredients or as contaminants of cosmetics, may react with the ethanolamines to form N-nitrosodiethanolamine (NDELA). NDELA has been found in cosmetic raw materials. Ninety-nine samples of 17 materials were evaluated and NDELA was detected in concentrations of greater than 1000 ppb, 501-l 000 ppb, 101-500 ppb, and 50-l 00 ppb in 6, 3,6, and 6 samples, respectively. NDELA was found in trace levels in nine samples and was not detected in 69 samples. (13*49) NDELA has also been detected in a variety of cosmetic products. (50-60) An on-going study by the FDA has provided NDELA analysis for 335 off-the-shelf cosmetic formulations. The FDA data are presented in Table 3. NDELA was detected in 110 of a total of 252 products containing TEA and in 25 of a total of 64 products not containing TEA. However, products with no TEA may have contained DEA or MEA. These findings suggest the possibility that TEA may lead to the formation of NDELA in some cosmetics.

Bronaugh et al.(61,62) investigated the percutaneous absorption of N DELA through excised human skin. NDELA was dissolved in water, propylene glycol, and isopropyl myristate, and the permeability constants were 5.5 x 10m6, 3.2 x

10m6, and 1.1 x 10m3 cm/h, respectively. The permeability of NDELA through ex-




TABLE 3. Association of NDELA with TEA in Cosmetics

Analyzed by the FDA.

Cosmetic product samples NDELA No NDELA

reported to contain detected detected

TEA 110 142

No TEA 25 39

Incomplete or no Ingredient information 5 14

-

(Total) 140 (Total) 195

Data from Refs. 51-55.

cised human skin was greatly increased when applied from sufficiently lipoidal formulations. The major route of elimination after oral and topical administration of NDELA to rats was the urine. (63) NDELA was applied to the skin of monkeys and pigs and, afterwards, was detected in their urine.(64) NDELA was detected in rat urine following epicutaneous and intratracheal administration of NDELA and following percutaneous administration of DEA and oral administration of nitrite in drinking water. (“) After application of an NDELA-contaminated cosmetic. NDELA was detected in human urine.‘66’

NDELA, in concentrations of 5-15 mg/plate, was mutagenic to Salmonella typhimurium strains TA1535 and TAlOO in the presence of hamster liver S-9 but not in the presence of rat liver S-9. (67) NDELA is carcinogenic to rats after oral administration’68-70) and to hamsters after subcutaneous injections, skin painting, and oral cavity swabbing. (71.72) Although no epidemiological data were available, the international Agency for Research on Cancer(73) has suggested that “NDELA should be regarded for all practical purposes as if it were carcinogenic to humans.”

Nitrites have been found in cosmetic raw materials.(L3.49.74) TEA and DEA can be nitrosated to NDELA with 2-bromo-2-nitropropane-1,3-diol (BNPD), an antimicrobial agent used in cosmetics. (75-77) A report on the safety assessment of BNPD recommended against its usage in cosmetics where its actions with amines or amides could result in the formation of nitrosamines or nitrosamides.‘75) Ong et al.(78) discovered that NDELA could be formed from the peroxidation and subsequent nitrosation of DEA. They found that peroxides could result from the autoxidation of compounds such as polysorbate 20 and that the addition of antioxidants prevented this. Under the same experimental conditions, TEA and MEA did not yield NDELA.

Noncosmetic Uses

The ethanolamines are used in the manufacture of emulsifiers and dispersing agents for textile specialties, agricultural chemicals, waxes, mineral and vegetable oils, paraffin, polishes, cutting oils, petroleum demulsifiers, and cement additives. They are intermediates for resins, plasticizers, and rubber chemicals. They are used as lubricants in the textile industry, as humectants and




softening agents for hides, as alkalizing agents and surfactants in pharmaceuticals, as absorbents for acid gases, and in organic syntheses.(5’6)

TEA, at a concentration not exceeding 2 ppm, and MEA, at a concentration not exceeding 0.3 ppm, may be used in flume water for washing sugar beets prior to slicing (21 CFR 173.315). TEA, DEA, and MEA, at no specific concentration limits, may be components of articles intended for use in producing, manufactur- ing, packing, processing, preparing, treating, packaging, transporting, or holding food(79) except that TEA and DEA may not exceed 5% by weight of rubber articles intended for repeated use. (‘O) TEA and DEA may be used as adjuvants for pesticide chemicals and are exempt from the requirement of tolerances(81) except that DEA maleic hydrazide may not be sold in the United States.(82)

GENERAL BIOLOGY

Antimicrobial Effects

TEA, DEA, ‘and MEA inhibit the growth of a wide variety of microorganisms. The concentration of ethanolamine required to inhibit growth varies with genus and species.(s,63-s7) DEA and MEA have some antimycotic activity when applied on the skin of guinea pigs.(88-90’

Effects on Chick Embryo

The incubation of chicken eggs with 0.03% MEA for 18 h increases the number of eggs with visible blastodisks, increases the synthesis of proteins, fats, and carbohydrates, and increases the number of hatching chicks.r9’)

Effects on Enzymatic Activity

Effects on Enzymes Involved in Lipid Biosynthesis

TEA, DEA, and MEA affect the biosynthesis of lipids. Reactions of particular interest in mammals are those involved in the synthesis of the phosphoglycerides, phosphatidylethanolamine (PE), phosphatidylcholine (lecithin) (PC), and phosphatidylserine (PS):‘92’

Ethanolamine + ATP ethanolamine kinase

> phosphoethanolamine + ADP

phos hoethanolamine cyti ylyltransferase *8

CTP + phosphoethanolamine - CDP-ethanolamine + PPi

phosphoethanolamine

transferase

CDP-ethanolamine + diacylglycerol -




phosphatidylethanolamine + CMP

Phosphatidylethanolamine + serine - \

phosphatidylserine + ethanolamine

choline kinase Choline + ATP > phosphocholine + ADP

phosphocholine cytidylytransferase

Phosphocholine + CTP > CDP-choline + PPi

phosphocholine transferase

CDP-choline + diacylglycerol phosphatidylcholice + CMP

The administration of MEA at a dose of 60 mg/kg/day for 30 consecutive days to albino rats with experimentally-induced coarction of the aorta resulted in elevated levels of PE, PS, and PC in the rat myocardium. Metabolic changes produced by MEA action may have inhibited the development of cardiac insufficiency in these animals.‘93’ Hale et al.(94’ grew chicken embryo fibroblasts in standard media with 40 mg/ml of choline in delipidated media without choline, and in delipidated media without choline and with 40 mglml of MEA. The PE content of the cells was increased in both delipidated media and hexose transport was slowed in the MEA supplemented medium. The authors suggested that some property of MEA other than its accompanying increase in PE must be responsible for the drop in hexose transport in these cells. Upreti(9s) injected intraperitoneally approximately 168 mglkg of MEA into male albino mice every day for four days. Mice were sacrificed at 6, 12, 24, 48, and 96 h. At all times from 12 to 96 h, the liver ethanol kinase levels of the treated mice were significantly higher than control mouse liver levels.

Barbee and Hartung(96) investigated the effect of the administration of DEA on the in vivo incorporation of MEA and choline into rat liver and kidney. They found that the administration of 250 mg/kg of labeled DEA in a single injection to male albino rats did not change the amount of injected labelled MEA and choline incorporated into liver or kidney. However, when labelled DEA was administered to male albino rats at a dose of 320 mg/kg/day in drinking water for up to three weeks, the results were different. Rats were sacrificed at 0, 1, 2, and 3 weeks, and the amounts of injected labeled MEA and choline incorporated in the liver and in the kidney were lower at 1, 2, and 3 weeks than at time 0. MEA and choline phospholipid derivatives were synthesized faster and in greater amounts, and were catabolized faster than DEA phospholipid derivatives. This may favor accumulation of DEA-containing phospholipids during chronic exposure. These researchers also investigated the effects of DEA on mitochondrial function in the male albino rat.(97) Administration of neutralized DEA at doses of 490 mglkglday for three days or of 160 mglkglday for one week in drinking water produced alterations of hepatic mitochondrial function. Barbee and Hartung hypothesize




that DEA phospholipids are formed and incorporated into mitochondrial membranes with subsequent disruption of mitochondrial metabolism.

The activity of glucosyltransferase, isolated from Streptococcus mutans

culture supernatant solutions, was stimulated by TEA at a concentration of 50 mM and a pH of 6.5. (98) Glucosyltransferase catalyzes the formation of glucocerebro- side, a sphingolipid, from ceramide and UDP-D-glucose.(92)

Effects on Other Enzymes

MEA inhibits the action of purified acetylcholinesterase from bovine erythro- cytes. (99) Acetylcholinesterase catalyzes the reaction of acetylcholine and water to acetic acid and choline. This enzyme functions in the activity of the nervous system .(92)

DEA administered intraperitoneally or orally may affect directly or indirectly the serum enzyme levels, isozyme patterns, and concentrations of some amino acids and urea in the male rat liver and kidney. These changes were observed concomitant with or just after organ damage was histologically detectable.(‘OO~‘O” Subchronic DEA administration in drinking water increased male rat hepatic mitochondrial ATPase and altered mitrochondrial structure and function.(97)

MEA stimulates the activity of purified aspartate transaminase from porcine heart(lo2) and intraperitioneal or intravenous administration of MEA decreases aspartate transaminase activity in rabbit kidney and heart.“03) The reversible reaction of L-aspartate and a-ketoglutarate to oxaloacetate and L-glutamate is catalyzed by aspartate transaminase.(92) Kotogyan et al.(‘04) found that the intravenous administration of MEA to rabbits for seven days increased the level of aspartate and glutamate in the kidneys and decreased the levels in the brain.

The intraperitoneal or intravenous administration of MEA to rabbits decreased the activity of alanine transaminase in the kidney and the heart.“03) Alanine trans-

-aminase is the enzyme involved in the reversible reaction that converts L-alanine and a-ketoglutarate to pyruvate and L-glutamate.(“)

lntraperitoneal administration of MEA to rats inhibited alcohol dehydrogenase. Ostroviskii and Bankovskii”“’ suggested that this was the reason for the hepatic accumulation of endogenous ethanol and taurine.

Peroxidase activity and number of organic peroxide molecules in the blood, liver, and homogenate of chick embryos were decreased when chicken eggs were incubated with MEA.‘9’) Peroxidase acts in reactions in which hydrogen peroxide is an electron acceptor.

MEA can inactivate and partially dissociate P-galactosidase from Escherichia co/i (‘O’) Beta-galactosidase catalyzes the formation of D-glucose and D-galactose from lactose and water.‘921

Effects on Hormones

MEA can affect the metabolism of catechol amines. The conversion of interest is as follows:

L-tyrosi ne - dihydroxyphenylalanine (DOPA) - dopamine - norepinephrine - epinephrine




Epinephrine and norepinephrine are hormones secreted by the adrenal medulla. They act in the regulation of heart rate and blood pressure. Epinephrine also activates glycogen breakdown to glucose in the liver and in muscle through its stimulation of adenylate cyclase. (92) lntraperitoneal injection of MEA into rats at 10 mglkg increased norepinephrine and decreased epinephrine in the heart. A 25 mglkg injection of MEA had the opposite effect. At the higher MEA dose, after three days the heart norepinephrine concentration remained altered and the DOPA concentration increased. (lo’) A 25 mg/kg intraperitoneal injection of MEA increased mouse heart muscle content of epinephrine and DOPA and decreased the content of norepinephrine.(108) Goncharenko et al.(109) found increased dopamine concentrations in rats following injection of MEA. DOPA decreased or remained unchanged.

Okano(llo) reported that the in vitro conversion of proparathyroid hormone formed in the parathyroid gland to parathyroid hormone was strongly inhibited by the action of MEA. Parathyroid hormone is involved in the metabolism of calcium and phosphorus by the body.

Effects on Protein, Nucleic Acids, and Other Cellular Substances

Subchronic oral administration of MEA to castrated rams increased serum albumin concentrations and total protein concentrations.‘“”

The administration of MEA to rabbits, either intraperitoneally or intrave- nously, increased RNA concentrations in the kidney, heart, and brain, decreased DNA concentrations in the heart and brain, and had no effect on total nitrogen or protein in any of the three tissues.(‘O’)

lntraperitoneal administration of MEA to rats increased glycogen, ATP, and ascorbic acid concentrations in the liver, kidney, brain, and heart.(‘12)

Effects on Liver Structure

Grice et al.(loo) assessed morphological damage to rat liver and kidney four and 24 h after intraperitoneal injection of DEA at 100 and 500 mglkg. At both times, after both doses and in both organs, cytoplasmic vacuolization was observed. In addition, mitochondria of the hepatocytes were swollen and less dense than in the control animals, and after 24 h, liver nuclei were more deeply basophilic than normal. At both times at the high dose of DEA, there was some renal tubular degeneration and some cells were necrotic. Barbee and Hartungt9’) found that the mitochondria from rats treated with 3 mglkglday of DEA for two weeks in their drinking water were consistently spherical and also appeared larger than mitochondria from control animals. Korsud et al.C1O1) administered 100 to 6400 mg/kg of DEA orally to rats. They discovered that liver and kidney weights and damage to the liver and kidney increased as dose increased. They confirmed the observations of Grice et al.(‘OO) except that they found no morphological differences in mitochondria from control and treated rats.

Effects on the Heart

MEA, administered to rats with experimentally-induced coarction of the aorta, at doses from 5 to 50 mglkg enhanced myocardial contractility. Thirty-day




administration of MEA in a dose of 10 mglkg stimulated and 60 mg/kg of MEA inhibited the development of myocardial hypertrophy.rg3) Increasing doses of MEA from 9.6 x 1 O-’ M to 1.2 x 1 Ow5 M increased the atrial rate and force of contrac- tion in the isolated rabbit atria.(‘13)

Effects on the Bovine Rhodopsin Chromophore

MEA bleached the visual pigment, rhodopsin, from water-washed bovine retinal rod chromophores, which are responsible for vision in dim light.“14)

ABSORPTION, METABOLISM, STORAGE, AND EXCRETION

MEA is the only naturally occurring ethanolamine in mammals and is excreted in the urine.“‘) Much of the available scientific literature on the metabolism of the ethanolamines is concerned with the effect on phospholipid biosynthesis of the intraperitoneal and intracerebral or in vitro administration of MEA to intact mammals or mammalian tissue, respectively. Ansell and Spanner(“‘) have performed a respresentative experiment. Labeled MEA was administered intraperitoneally to adult female rats, the rats were sacrificed, and incorporation of MEA into phospholipids was traced in the liver, the blood, and the brain. They discovered that MEA was converted to phosphatidylethanolamine (PE) in all the tissues. However, the step-wise methylation of PE that converts it to phosphatidylcholine (PC), which occurs rapidly in the liver and less rapidly in ex- trahepatic tissues, did not occur at all in the brain. Morin”“’ found that labelled MEA was incorporated into PE and also into PC in isolated human peripheral arteries. This suggests that the enzyme system for transmethylation of PE to PC may be active in human arteries. Researchers have found labeled respiratory carbon dioxide after intraperitoneal administration of labeled MEA to rats.(“” Fur- ther sources are available that corroborate these findings on the effect of MEA on lipid biosynthesis in mammals.~‘05~11sJ-140)

In vitro administration of MEA had no effect on the incorporation of labeled phosphate into phospholipids in swine coronary and pulmonary arteries”4” or in rabbit or human endometria. (14*) However, in both cases TEA did inhibit the incorporation of labeled phosphate into phospholipids.

Babior(‘43) labeled purified MEA from an unspecified source and demonstrated a coenzyme-B12-dependent ethanolamine deaminase mediated conversion of MEA to acetaldehyde and ammonia. Ostrovskii and Bankovskii”“’ administered MEA intraperitoneally to rats and observed an increase in blood urea and brain glutamine. They suggested that ethanolamine was an ammonia source. Sprinson and Weliky (1441 labeled MEA and administered it in feed to rats. They detected labeled acetate in the urine of the rats. They suggested that MEA is phosphorylated by ATP in vivo, converted to acetaldehyde, ammonia, and inorganic phosphate and then the acetaldehyde is oxidized to acetate. These researchers hypothesize that the removal of phosphorylated MEA by its conversion to acetate may exert a regulatory effect on PE biosynthesis.

Labeled MEA was administered to dogs. The route of administration was unspecified. After 24 h, the total blood radioactivity as a percentage of dose was




1.69%. There was a persistence of low levels of radioactivity in dog whole blood samples; the half-life was 19 days. Excretion in urine of radioactivity as a percentage of dose was 11 'Yo.(~~')

ANIMAL TOXICOLOGY

Oral Studies

Acute Toxicity

The acute oral toxicity of TEA, DEA, MEA, and a hair preparation containing DEA and MEA has been studied in guinea pigs(146-‘4g’ and in rats.(‘49-‘59) The animals were administered the material by gavage, and then were observed for 14 days. Table 4 presents data from the experiments. The LD50 values for rats of TEA, DEA, and MEA ranged from 4.19 g/kg to 11.26 g/kg, 0.71 ml/kg to 2.83 g/kg, and 1.72 g/kg to 2.74 g/kg, respectively. The LD50 values for DEA and MEA are quite similar and are lower than the LD50 values for TEA. In the Hodge and Sterner(‘60) classification of single-dose oral toxicity for rats, TEA, DEA, and MEA would be classified as practically nontoxic to slightly toxic, slightly toxic, and slightly toxic, respectively.

Oral Corrosivity

A study was conducted on rabbits to determine the oral tissue corrosivity potential of a hair preparation containing 1.6% DEA, 5.9% MEA, and 3.2% sodium borate.““” The undiluted test material at a dose of 0.229 g/kg (0.210 ml/kg) was placed on the posterior tongue surface of four rabbits and they were allowed to swallow. Two rabbits were sacrificed at 24 h and two at 96 h. Gross and microscopic examinations of the tongue, adjacent pharyngeal structures, larynx, esophagus extending to the cardiac incisure, and stomach revealed no observable abnormalities. The hair preparation was not an irritant and was not corrosive in these tests.

Subchronic and Chronic Toxicity

Long-term oral toxicity of TEA, DEA, MEA or a composite of hair dyes and bases has been studied in guinea pigs,(‘49) in rats~‘49~‘55~‘56~‘6z~‘6s~ and in dogs.(‘66) Table 5 presents data from the experiments. Considerably less data are available for DEA and MEA than for TEA. However, it does appear that DEA is the most toxic ethanolamine. Workers at the Mellon Institute (‘54) have suggested that this may be because MEA has a normal function in the lipid metabolism of the body and DEA is structurally similar enough to MEA to act in competition with it and interfere in lipid metabolism. TEA may be so sufficiently unlike MEA that it does not act in competition and therefore is less toxic than DEA.

Acute Toxicity

Dermal Studies

than Undiluted TEAS, 91.8% and 88.1% active and both containing slightly more 6% of DEA, were each applied to the intact skin of three rabbits and to the



TAB

LE

4.

Ac

ute

O

ral

Toxi

city

.

Ma

teria

l te

ste

d

Co

w.

of

ma

teria

l te

ste

d (

%)

an

d v

eh

icle

Do

se

of

No

. a

nd

sp

ec

ies

eth

an

ola

min

ea

o

f a

nim

al

LD50

C

om

me

nts

Ref.

TEA

, VV+

Perc

ent

20

in

wa

ter;

100

4.0; 5.0, 6.3 g/k

g

2 ra

ts

at

ea

ch

do

se

leve

l

TEA

, VV+

Perc

ent

TEA

, 70

.6%

(DEA

, 8.

6%;

MEA

, 1.

7%)

TEA

, 91

.8%

(DEA

, 6.

5%)

TEA

, 88

.1%

(DEA

, 6.

1%)

TEA

, C

om

me

rcia

l

or

hig

h

pu

rity

gra

de

In

gum

a

rab

ic

solu

tion

25

in

wa

ter

100

0.6-7.0

g/k

g

2.6-

7.4

ml/

kg

TEA

3.64

-14.

00

ml/

kg

100

3.64-10.00

ml/

kg

100

1 .O

-26.

0 g

/kg

TEA

, C

om

me

rcia

l 10

0

gra

de

1.0-12.0

g/k

g

2-3

(un

spe

cifi

ed

) g

uin

ea

pig

s a

t e

ac

h d

ose

le

vel

10

rats

a

t e

ac

h o

f 4

do

se

leve

ls

10

rats

a

t e

ac

h o

f 5

do

se

leve

ls

10

rats

a

t e

ac

h o

f 4

do

se

leve

ls

10

gui

ne

a

pig

s a

t LD

50

an

d a

t 1

g <

LD

50

est

ima

ted

fro

m

sing

le

fee

din

gs

10

rats

a

t LD

50

an

d a

t

1 g

<

LD50

e

stim

ate

d

from

sin

gle

fe

ed

ing

s

4.03

m

l/kg

(4.19

g/k

g)

7.11

m

l/kg

5.39 m

l/kg

8 slk

g

012,

11

2, 2

12 d

ea

ths,

mo

de

rate

liv

er

an

d

kid

ne

y d

am

ag

e a

t a

ll

do

se

leve

ls.

All

surv

ive

d

0.6

an

d

1.4

g/k

g;

No

ne

surv

ive

d

7.0

g/k

g.

150

146

No

u

nu

sua

l o

bse

rva

tions

. 15

1

Slig

ht

to

mo

de

rate

d

eg

ree

s

of

hem

orrh

ag

ic

rhin

itis

in

rats

d

ose

d

at

~7.1

4

ml/

kg.

Slig

ht

to

mo

de

rate

d

eg

ree

s

of

hem

orrh

ag

ic

rhin

itis

in

rats

do

sed

a

t ~7

.14

ml/

kg.

Gro

ss

pa

tho

log

y c

on

fine

d

to

inte

stin

al

tra

ct.

Befo

re

de

ath

, d

iarr

he

a

an

d

pro

stra

tion

ob

serv

ed

in

mo

st

an

ima

ls.

Som

e

we

re

pa

raly

zed

in

the

ir h

ind

qua

rte

rs.

Gro

ss

pa

tho

log

y c

on

fine

d

to

inte

stin

al

tra

ct.

Befo

re

de

ath

, d

iarr

he

a

an

d

pro

stra

tion

ob

serv

ed

in

mo

st

an

ima

ls.

152

152

149

149



TAB

LE

4.

(Co

ntin

ue

d.)

Ma

teria

l te

ste

d

CO

W.

-of

ma

teria

l

test

ed

(%

)

an

d v

eh

icle

Do

se

of

eth

ano

/am

ine

a

No

. a

nd

sp

ec

ies

of

an

ima

l LD

50

Co

mm

ent

s Re

f.

TEA

, h

igh

p

urit

y

gra

de

TEA

in

wa

ter

TEA

, p

rod

uce

d

from

19

39-l

960

20

in w

ate

r/l0

0

DEA

, 99

+ Pe

rce

nt

DEA

DEA

DEA

DEA

, p

rod

uce

d

from

19

39-1

949

100

in

gum

a

rab

ic

solu

tion

in w

ate

r

100

100

20

in w

ate

r

I .0

-l 2.

0 g

lkg

10

ra

ts

at

LD50

a

nd

at

1 g

<

LD50

e

stim

ate

d

from

sin

gle

fe

ed

ing

s

6 m

ale

ra

ts

at

ea

ch

do

se

leve

l

rats

0.6-

5.0

g/k

g

2-3

(un

spe

cifi

ed

) g

uin

ea

pig

s a

t e

ac

h d

ose

le

vel

6 m

ale

ra

ts

at

ea

ch

do

se

leve

l

5 fe

ma

le

rats

a

t e

ac

h

do

se

leve

l

5 fe

ma

le

rats

a

t e

ac

h

do

se

leve

l

90-l

20

(un

spe

cifi

ed

) ra

ts

9 d

ke

9.11

g

/kg

8.54

-9.8

5

ml/

kg

or

7.3-

l 1.

26

glk

g

1 .a

2 g

/kg

0.80

m

l/kg

0.71

ml/

kg

1.41

-2.8

3

g/k

g

Gro

ss

pa

tho

log

y c

on

fine

d

to

inte

stin

al

tra

ct.

Befo

re

de

ath

, d

iarr

he

a

an

d

pro

stra

tion

ob

serv

ed

in

mo

st

an

ima

ls.

All

surv

ive

d

6.0

an

d

1 .O

g/k

g;

No

ne

surv

ive

d

3.0

g/k

g.

149

156

154,

155

147

156

157

158

154



MEA

, 99

+ Pe

rce

nt

in g

um

ara

bic

0.

64-l

.4 g

/kg

2.

3 (u

nsp

ec

ifie

d)

gui

ne

a

All

surv

ive

d

0.6

g/k

g;

No

ne

148

solu

tion

pig

s a

t e

ac

h d

ose

le

vel

surv

ive

d

7.0

g/k

g.

MEA

in

wa

ter

6 m

ale

ra

ts

at

ea

ch

do

se

2.74

g

/kg

15

6

leve

l

MEA

m

ale

ra

ts

I .9

7 g

/kg

15

9

MEA

fe

ma

le

rats

1.

72

g/k

g

159

MEA

, p

rod

uce

d

20

in w

ate

r 90

-l 20

(u

nsp

ec

ifie

d)

rats

2.

14-2

.74

154

from

19

39-l

949

g/k

g

____

____

____

____

____

____

____

____

____

____

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

---

__

_---

--

Ha

ir p

rep

ara

tion

10

0 8.

72-l

7.4

g/k

g

10

rats

a

t e

ac

h o

f 4

do

se

14.1

g

/kg

A

nim

als

rec

eiv

ing

b 1

3.8

dkg

16

7

(DEA

, 1.

6%;

(8.0

0-l

6.0

leve

ls

(12.

9 m

l/k@

o

f p

rod

uct

ha

d s

igns

o

f

MEA

, 5.

9%;

ml/

kg)

of

for

un

di-

me

lan

uria

, d

iarr

he

a,

sod

ium

b

ora

te,

un

dilu

ted

lu

ted

pre

p

po

lyu

ria,

an

d d

isco

lora

tion

3.2%

) p

rep

ara

tion

p

ara

tion

of

sto

ma

ch,

in

test

ina

l

muc

osa

, a

nd

ga

stro

inte

s-

tina

l c

ont

ent

s.

aA

dju

ste

d

for

co

nce

ntra

tion

test

ed

a

nd

ma

teria

l a

ctiv

ity,

wh

en

kn

ow

n.



TAB

LE

5.

Sub

ch

ron

ic

an

d

Ch

ron

ic

Toxi

city

.

Ma

teria

l te

ste

d

Do

se

an

d v

eh

icle

Le

ngth

o

f st

udy

No

. a

nd

sp

ec

ies

of

an

ima

ls Re

sults

Re

f.

TEA

O

-2.6

1 g

/kg

/da

y

in f

oo

d

90

da

ys

10

rats

at

ea

ch

d

ose

le

vel

TEA

, 88

.5%

O

-l .O

glk

gld

ay

(DEA

, 6%

) in

fo

od

TEA

, c

om

me

rcia

l

or

hig

h

pu

rity

gra

de

0.2-

l .g

g/k

g/d

ay

in f

oo

d

91

da

ys

60,

120

da

ys

20

rats

o

f e

ac

h

sex

at

ea

ch

of

4 d

ose

le

vels

8 ra

ts

of

ea

ch

do

se

leve

l fo

r

ea

ch

tim

e

No

e

ffe

cts

o

bse

rve

d

at

~0.0

8 g

/kg

/da

y.

De

cre

ase

d

we

igh

t g

ain

at

1.27

g

/kg

/da

y.

He

avy

liv

ers

a

nd

kid

ne

ys

pro

duc

ed

w

he

n

do

se

wa

s ~0

.17

g/k

g/d

ay.

Ma

jor

pa

tho

log

y

of

sma

ll in

test

ine

, ki

dn

ey,

liv

er,

or

lun

g

rare

at

~0.7

3 g

/kg

/da

y. M

ost

m

ajo

r p

a-

tho

log

y o

bse

rve

d

wa

s fa

tty

de

ge

nera

tion

of

the

liv

er.

Som

e

de

ath

s a

t ~0

.73

g/k

g/d

ay.

Inc

rea

sed

w

eig

ht

ga

in

in f

em

ale

ra

ts

rec

eiv

ing

0.25

g

/kg

/da

y.

Inc

rea

sed

fe

ed

co

nsum

ptio

n

in f

em

ale

ra

ts

rec

eiv

ing

0.

5 g

/kg

/da

y.

No

sign

ific

an

t d

iffe

renc

es

note

d i

n o

rga

n to

bo

dy

we

igh

t ra

tios.

N

o

gro

ss

or

hist

op

ath

olo

gic

ind

ica

tion

s o

f a

tre

atm

ent

re

late

d

eff

ec

t.

No

sig

nifi

ca

nt

hem

ato

log

ic

eff

ec

ts.

Perip

he

ral

op

tic

ne

rve

s sh

ow

ed

sc

att

ere

d

de

-

ge

nera

tion

in t

he

mye

lin

of

ind

ivid

ua

l fib

ers

at

all

do

ses

for

bo

th

60

an

d

120

da

ys.

Live

r

cha

nge

s w

ere

o

bse

rve

d

at

~0.4

g

/kg

/da

y

for

60

or

120

da

ys.

Kid

ne

y c

hang

es

we

re

ob

serv

ed

a

t 0.

2 to

0.2

25

g/k

g/d

ay

for

120

da

ys a

nd

at

0.4-

0.45

g

/kg

/da

y fo

r 60

o

r

120

da

ys.

Kid

ne

y d

am

ag

e w

as

ob

serv

ed

a

t

~0.8

g

/kg

/da

y fo

r 60

o

r 12

0 d

ays

. N

o

kid

ne

y d

am

ag

e w

as

seve

re

eno

ugh

to

inte

rfe

re

with

o

rga

n fu

nctio

n.

154,

156

163

149



TEA

, c

om

me

rcia

l

or

hig

h

pu

rity

gra

de

0.2-

l .8

g

/kg

/da

y

in f

oo

d

TEA

, c

om

me

rcia

l 0.

2-l

.6 g

/kg

/da

y

or

hig

h

pu

rity

by

pip

ett

e

gra

de

5

da

ys/w

ee

k

TEA

, c

om

me

rcia

l

or

hig

h

pu

rity

gra

de

TEA

, 99

%

0.2-

l .6

g/k

g/d

ay

by

pip

ett

e

5 d

ays

/we

ek

1.4

mg

ll in

drin

kin

g

wa

ter;

TEA

in

drin

kin

g

wa

ter

an

d 6

.5%

TEA

so

lutio

n

ap

plie

d

to

skin

ca

ud

ally

fo

r 1

h

5 d

ays

/we

ek;

TEA

in

drin

kin

g

wa

ter

an

d

13%

TEA

so

lutio

n

ap

plie

d

to

skin

ca

ud

ally

fo

r 1

h

120

da

ys a

nd

the

n,

-3

mo

nths

w

ith-

out

TE

A

60,

120

do

ses

120

do

ses

an

d

the

n,

-3

mo

nths

w

ith-

out

TE

A

6 m

ont

hs

8 ra

ts

at

ea

t h

do

se

leve

l

8 g

uin

ea

p

igs

at

ea

ch

do

se

leve

l fo

r e

ac

h

num

be

r o

f

do

ses

8 g

uin

ea

p

igs

at

ea

ch

do

se

leve

l

10

rats

in

ea

ch

ww

Kid

ne

y re

ge

nera

tion

wa

s o

bse

rve

d

aft

er

org

an

da

ma

ge

.

149

Perip

he

ral

op

tic

ne

rve

s sh

ow

ed

sc

att

ere

d

de

ge

nera

tion

in t

he

mye

lin

of

ind

ivid

ua

l

fibe

rs

at

all

do

ses

for

bo

th

60

an

d

120

da

ys.

Live

r a

nd

kid

ne

y d

am

ag

e w

as

ob

serv

ed

a

t

~0.8

g

/kg

/da

y.

No

ki

dn

ey

or

live

r d

am

ag

e

wa

s se

vere

e

noug

h to

in

terf

ere

w

ith

org

an

func

tion.

149

Live

r a

nd

kid

ne

y re

ge

nera

tion

wa

s o

bse

rve

d

aft

er

org

an

da

ma

ge

.

149

No

to

xic

e

ffe

ct

ob

serv

ed

fro

m

6.5

pe

rce

nt

top

ica

l TE

A

an

d

1.4

mg

/l T

EA

in d

rinki

ng

wa

ter.

Cha

nge

s o

bse

rve

d

aft

er

1 m

ont

h in

the

fu

nctio

ns

of

the

liv

er

an

d c

ent

ral

ne

rvo

us

syst

em

in

an

ima

ls re

ce

ivin

g

13%

top

ica

l TE

A

an

d 1

.4

mg

/l T

EA

in

drin

kin

g

wa

ter.

Inc

rea

se

see

n in

nu

mb

er

of

seg

-

me

nte

d

ne

utro

ph

ils

aft

er

3 m

ont

hs

an

d

inc

rea

se

see

n in

nu

mb

er

of

lym

ph

oc

yte

s

aft

er

4 m

ont

hs.

165

* E

El

r z . . ;;1

P

0 3 : 3 F Distributed for Comment Only -- Do Not Cite or Quote


TABL

E 5.

(C

ont

inue

d.)

Ma

teria

l te

ste

d

Do

se

an

d v

eh

icle

5 d

ays

/we

ek.

DEA

, n

eut

raliz

ed

1

.o,

2.0,

3.

0

salt

(lab

ele

d)

m M

/kg

/da

y

ora

lly

Leng

th

of

stud

y

11

da

ys

(5th

-

15th

d

ay

aft

er

birt

h)

No

. a

nd

sp

ec

ies

of

an

ima

ls

Ne

ona

tal

rats

Resu

lts

No

c

hang

es

ob

serv

ed

in

he

art

o

r b

rain

.

Mo

de

rate

c

lou

dy

swe

llin

g

see

n in

ki

dn

ey

pro

xim

al

tub

ule

. Pe

ripo

rta

l c

lou

dy

swe

llin

g

an

d v

ac

uo

liza

tion

se

en

in

live

r. Sw

olle

n

he

pa

tic

mito

cho

ndria

o

bse

rve

d.

Ma

ny

de

ath

s o

bse

rve

d.

The

re

wa

s liv

er

an

d

kid

ne

y d

am

ag

e a

nd

a p

ron

oun

ce

d

norm

oc

ytic

an

em

ia

with

ou

t b

one

m

arr

ow

d

ep

letio

n

or

ob

vio

us

inc

rea

se

in

num

be

r o

r re

ticul

oc

yte

s.

Ref.

162

DEA

, n

eut

raliz

ed

4

mg

/ml

in

drin

kin

g

wa

ter

7 w

ee

ks

Ma

le

rats

16

4

DEA

O

-O.6

8 g

/kg

/da

y

in f

oo

d

90

da

ys

10

rats

a

t e

ac

h

do

se

leve

l

No

e

ffe

cts

o

bse

rve

d

at

~0.0

20

glk

gld

ay.

H

ea

vy

live

rs

an

d k

idn

eys

p

rod

uce

d

at

r0.0

90

g/k

g!

da

y. M

ajo

r p

ath

olo

gy

of

sma

ll in

test

ine

,

kid

ne

y,

live

r, o

r lu

ng

o

bse

rve

d

at

~0.1

7

g/k

g/d

ay.

M

ajo

r p

ath

olo

gy

inc

lud

ed

c

lou

dy

swe

llin

g

an

d d

eg

ene

ratio

n o

f ki

dn

ey

tub

ule

s

an

d l

ive

r fa

tty

de

ge

nera

tion.

So

me

a

nim

als

die

d

at

0.17

a

nd

0.3

5 g

lkg

lda

y a

nd

all

die

d

at

leve

ls

gre

ate

r th

an

tha

t.

154,

156

____

____

__--

____

-__-

---

---_

____

____

__-_

____

____

____

____

____

____

----

----

----

----

----

----

----

----

----

----

----

----

----

----

--

---

MEA

O

-2.6

7 g

/kg

/da

y 90

d

ays

10

ra

ts

at

ea

ch

N

o

eff

ec

ts

ob

serv

ed

a

t ~0

.32

glk

gld

ay.

H

ea

vy

154,

156

in f

oo

d

do

se

leve

l liv

ers

a

nd

kid

ne

ys

pro

duc

ed

a

t ~0

.64

dke

/

da

y. S

om

e

de

ath

s a

nd

ma

jor

pa

tho

log

y a

t

b 1

.28

g/k

g/d

ay.

__

____

____

____

____

__--

----

----

----

----

----

----

----

----

----

----

--

____

____

____

____

____

____

____

____

____

____

----

----

----

----

----

Co

mp

osit

e

ha

ir o

-O.0

975

g/k

g/d

ay

2 ye

ars

12

b

ea

gle

do

gs

No

to

xic

e

ffe

cts

o

bse

rve

d.

166

%

of

co

mp

osit

e

in

at

ea

ch

of

z d

yes

an

d b

ase

s ;;

(MEA

, 22

fo

od

3

do

se

leve

ls.

5 p

erc

ent

)

%

<

;;;

s




abraded skin of three rabbits. The test was a 24 h closed patch test and the TEAS were applied to yield a rabbit exposure of 2 g/kg of actual TEA. The 88.1% TEA elicited mild erythema and no edema at 24 h and the skin returned to normal by Day 6. The 91.8% TEA produced moderate erythema and no edema at 24 h and the treated sites were normal by Day 10. The animals were observed for 14 days. All rabbits gained weight and none died.(16*’

Subchronic and Chronic Toxicity

Kindsvatter(‘4g) applied commercial and high purity grades of TEA each to the shaved skin of 10 guinea pigs. The test was a closed patch continuous exposure test in which 8 g/kg was applied daily for five days a week to guinea pigs. Deaths occurred at from 2 to 17 applications. No guinea pigs survived 17 applications. Adrenal, pulmonary, hepatic, and renal damage was observed.

Kostrodymova et al. (16s) applied TEA caudally to rats for 1 h, five days per week, for six months. No toxic effects were observed with a 6.5% solution of TEA. A 13% solution of TEA did effect changes in the liver and central nervous system function. The toxic effect of TEA was not increased when rats were given 1.4 mg/l of TEA in their drinking water in addition to the dermal application of the 13% solution of TEA.

The percutaneous application of MEA to rats at a dose of 4 mglkglday resulted in nonspecific histological changes in the heart and lung. Hepatoxic manifestations included fatty degeneration of the liver parenchyma and subsequent focal necrosis.(169)

Groups of 16 rabbits had a cosmetic formulation containing 14% TEA stearate and 1% methycellulose, applied to one of two clipped sites on their backs that were alternated weekly, at doses of 1 and 3 ml/kg five times per week for 13 weeks. Mild to moderate skin irritation which cleared within 72 h was observed and this was followed by moderate to heavy skin scaling. No toxic effects were seen in any rabbits. The control rabbits received 3 mg/ml of 1% methylcellulose in water. The low dose group had significantly lower kidney weights and the high dose group gained less weight and had significantly greater kidney weights than the control rabbits.(ls3)

Burnett et aI. applied three hair dyes containing O.lO%-0.15% TEA, 1.500% TEA, or 2.0% DEA to the backs of groups of 12 rabbits for 13 weeks. The doses were 1 mg/kg twice weekly and two clipped sites were alternated. The skin of half the rabbits was abraded. The dye was placed on the skin, the rabbits were restrained for 1 h, then shampooed, rinsed and dried. Control rabbits were treated identically except that no dye was applied to their skin. No systemic toxicity was observed and there was no histomorphologic evidence of toxicity in the treated rabbits after 13 weeks.

Primary Skin Irritation

Rabbits were used in primary skin irritation studies for TEA,(“‘*“*) DEA,(‘73.‘74) and MEA (“So”) Data from these experiments are presented in Table 6. These data suggest that MEA is irritating to rabbit skin, and that TEA and DEA are much less irritating to rabbit skin than MEA.



TABL

E 6.

Pr

ima

ry

Skin

Ir

rita

tion

.

Ma

teria

l te

ste

d

Co

nce

ntra

tion

w

Me

tho

d

TEA

, 99

+ p

erc

ent

10

0 10

0.1

m

l o

pe

n a

pp

lica

tion

s to

the

e

ar

ove

r 14

da

ys.

10

24-h

our

se

mio

cc

lud

ed

pa

tch

ap

plic

atio

ns

to t

he

inta

ct

sha

ved

ab

do

me

n.

TEA

, 99

+ p

erc

ent

lo

o

TEA

10

0

3 24

-ho

ur

sem

ioc

clu

de

d

pa

tch

ap

plic

atio

ns

to t

he a

bra

de

d s

ha

ved

a

bd

om

en.

1 24

-ho

ur

oc

clu

de

d

pa

tch

ap

plic

atio

n

to

clip

pe

d

ba

ck.

Er

ythe

ma

(0

to

4),

e

de

ma

(0 t

o 4

),

an

d n

ec

rosis

(0

to

15

) e

valu

-

atio

ns

are

ma

de

at

24

an

d 7

2 ho

urs

an

d

are

ad

de

d a

nd

div

ide

d

by

2 to

yie

ld

a

prim

ary

irr

itatio

n

sco

re

(sc

ale

=

0

to

24).

Tota

l p

oss

ible

sc

ore

fo

r 22

la

bo

rato

ries

wa

s 40

0.

Num

be

r o

f

rab

bits

Re

sults

Re

f.

Un

spe

cifi

ed

Un

spe

cifi

ed

8 .m

ale

/ea

ch

lab

ora

tory

Slig

ht

hyp

ere

mia

a

fte

r

7 a

pp

lica

tion

s.

“Slig

ht

to

mo

de

rate

ly

irrita

ting

,

pro

long

ed

o

r re

pe

ate

d

exp

osu

re

ma

y b

e i

rrita

ting

.”

Mo

de

rate

h

ype

rem

ia,

ed

em

a,

an

d

nec

rosis

. “S

light

to

mo

de

rate

ly

irrita

ting

, p

rolo

nge

d

or

rep

ea

ted

exp

osu

re

ma

y b

e i

rrita

ting

.”

Prim

ary

irr

itatio

n

sco

res

rang

ed

from

0

to

5.5

for

22

lab

ora

torie

s.

Tota

l sc

ore

fo

r a

ll 22

la

bo

rato

ries

wa

s 27

.3.

171

171

172

____

---_

____

____

____

____

____

____

____

____

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----



I P

D

EA,

99 +

p

erc

ent

10

0 10

0.1

m

l o

pe

n a

pp

lica

tion

s to

the

e

ar

Un

spe

cifi

ed

So

me

d

ena

tura

tion

on

ea

r a

fte

r 17

3

ove

r 14

da

ys.

10

24-h

our

se

mio

cc

lud

ed

10

d

ose

s a

nd

on

be

lly

aft

er

2 p

atc

h a

pp

lica

tion

s to

the

sh

ave

d

3 d

ose

s.

“Mo

de

rate

ly

irrita

ting

.”

P D

EA,

99+

pe

rce

nt

10

in w

ate

r a

bd

om

en.

U

nsp

ec

ifie

d

No

irr

itatio

n

ob

serv

ed

. 17

3

DEA

, 99

+ p

erc

ent

50

i

6 Es

sent

iah~

no

irri

tatio

n

of

the

sk

in.

1’74

. 5

Sem

ioc

clu

de

d

pa

tch

ap

plic

atio

ns

to

inta

ct

Prim

ary

/ irr

itatio

n

sco

re

=

0.17

. 0

an

d a

bra

de

d s

ha

ved

sk

in.

Eryt

hem

a

an

d

“No

t a

prim

ary

irr

itant

.”

3

DEA

, 99

+ p

erc

ent

30

e

de

ma

re

ac

tions

a

re e

valu

ate

d

at

24

an

d

6 Es

sen

tially

no

irri

tatio

n

of

the

sk

in.

174

72

h a

nd

va

lue

s a

re a

vera

ge

d t

o y

ield

a

F

Prim

ary

irr

itatio

n

sco

re

=

0.29

. p

rima

ry

irrita

tion

sc

ore

(s

ca

le

=

0 to

8)

. “N

onc

orro

sive

to

ski

n.”

__

____

_ __

____

____

____

____

____

____

____

____

____

__--

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

MEA

, 99

+ p

erc

ent

85

, 10

0 Se

mio

cc

lud

ed

p

atc

h a

pp

lica

tion

s to

in

tac

t 1

Vis

ible

d

est

ruc

tive

a

ltera

tion

of

the

17

6

an

d a

bra

de

d s

ha

ved

sk

in.

Rea

ctio

n tis

sue

a

t th

e

site

o

f a

pp

lica

tion

.

eva

lua

ted

a

t 4

h.

“Co

rrosiv

e.”

MEA

, 99

+ p

erc

ent

30

Se

mio

cc

lud

ed

p

atc

h a

pp

lica

tion

s to

in

tac

t 6

Vis

ible

d

est

ruc

tive

a

ltera

tion

of

the

17

7

an

d a

bra

de

d s

ha

ved

sk

in.

Rea

ctio

n tis

sue

a

t th

e

site

o

f a

pp

lica

tion

a

t

eva

lua

ted

a

t 4

an

d a

t 24

h.

4

h.

Ne

cro

sis

ob

serv

ed

a

t 24

h.

“Co

rrosiv

e

to

skin

.”

MEA

, 99

+ p

erc

ent

l-1

00

10 0

.1

ml

op

en

ap

plic

atio

ns

to t

he

ea

r U

nsp

ec

ifie

d

10

pe

rce

nt

or

hig

he

r w

as

co

rro

sive

17

5

ove

r 14

d

ays

, TO

24-

hour

se

mio

cc

lud

ed

to

the

sk

in,

> 1

%

wa

s e

xtre

me

ly

pa

tch

ap

plic

atio

ns

to t

he

sha

ved

irr

itatin

g

to t

he

skin

a

nd

1%

w

as

ab

do

me

n.

irrita

ting

to

the

sk

in.

“Ext

rwn

eljx

co

rro

sive

to

sk

in.”




Phototoxicity

The phototoxicity of a suntan lotion containing 1% TEA was evaluated by applying the lotion to the stripped ears of six guinea pigs. A known photosensitizer was used as a positive control in four other guinea pigs. Each animal was then exposed to ultraviolet (UVA) from two GE F8T5-BL lamps at a distance of 4-6 cm for 2 h. No erythema or edema was observed in any of the guinea pigs treated with suntan lotion. Results of the positive controls are unavailable.“7s’

Skin Sensitization

Pairs of guinea pigs were treated dermally with 5%-100% TEA in water for 6 h with occlusion, and the treated sites were scored for erythema at 24 and 48 h. Since use of undiluted TEA resulted in only one erythemic reaction at 24 h, 100% TEA was used in both induction and challenge procedures in the subsequent sensitization test. Twenty guinea pigs received dermal applications of undiluted TEA once per week for three weeks. A challenge patch was applied after 14 days and again seven days later. One erythemic reaction occured in each of three animals during the induction procedure, in two other animals during the first challenge, and in one other animal during the second challenge. All the guinea pigs remained healthy and made normal weight gains during the test. There was no evidence of any skin sensitizing activity of undiluted TEA for guinea pigs.(“‘)

TEA from four different suppliers was evaluated in guinea pig skin sensitization tests.(180-‘83’ The tests were conducted with 10 control and 20 treated guinea pigs. The induction patches were applied once a week for up to six hours for three weeks. Two weeks later challenge patches were applied to both control and treated guinea pigs. One test was conducted with undiluted TEA at induction and 90% TEA at challenge’181’ and all the other tests were conducted with 50% TEA at induction and 90% TEA at challenge. (180,182*183) None of the animals showed clinicalsymptoms during or after the treatment period and no guinea pigs showed signs of primary irritation of the skin. Challenge reactions were measured with a reflectometer and average readings between control and experimental animals were compared. TEA was not a guinea pig skin sensitizer in these studies.

Patches containing a 25% active TEA solution and 10% and 5% TEA in aqueous solution were applied to the backs of four clipped guinea pigs. No irritation was observed in this preliminary study. Induction patches containing the 25% TEA solution were applied to the backs of 20 clipped guinea pigs for 6 h once per week for three weeks. One week later, a challenge patch containing 25% TEA was applied for 6 h to the clipped backs of the 20 treated and 10 control guinea pigs. Challenge reactions were read at 24 h and at 48 h. No irritation was observed. No positive primary irritation or sensitization responses were observed under the test conditions with the 25 percent active TEA soIution.(184)

Eye Irritation

The eye irritation potential of TEA, DEA, MEA, or cosmetic products containing the ethanolamines has been studied in rabbits(17*~‘72~174~‘77~1~s~1”7) and in rhesus monkeys. (la8) Data from these experiments are presented in Table 7. In high concentrations and with long contact time, TEA, and DEA may be irritating to the rabbit eye and MEA is irritating to the rabbit eye.



TABL

E 7.

Ey

e

Irrita

tion.

Co

nce

ntra

tion

Ma

teria

l te

ste

d

w

Me

tho

d

No

. a

nd

spe

cie

s

of

an

ima

ls Re

sults

Re

f.

TEA

, 99

+ p

erc

ent

10

0

TEA

, 99

+ p

erc

ent

10

in

wa

ter

ml

of

test

m

ate

rial

inst

ille

d

into

c

on

jun

ctiv

al

sac

of

bo

th

rab

bit

eye

s.

Left

e

ye u

nw

ash

ed

. A

fte

r

30

sec

. e

xpo

sure

, rig

ht

eye

wa

she

d

for

2 m

in

with

ta

p w

ate

r.

TEA

10

0

TEA

, 98

p

erc

ent

10

0

0.00

5,

0.02

m

l o

f te

st m

ate

rial

ap

plie

d

to c

orn

ea

1 c

ent

er

wh

ile

eye

lids

are

retr

ac

ted

. Li

ds

rele

ase

d

aft

er

1 m

in.

Eye

in

jury

sc

ore

d

on

a s

ca

le o

f 0

to

20

po

ints

a

fte

r 18

-24

h.

0.01

, 0.

03,

0.10

m

l o

f te

st

ma

teria

l

ap

plie

d

dire

ctly

to

co

rne

a

an

d

eye

lids

rele

ase

d

imm

ed

iate

ly.

Eye

s

sco

red

a

t d

ays

1,

3,

7,

14

an

d 2

1

by

the

m

eth

od

o

f D

raiz

e,

et

al.“

“’

(sc

ale

=

0

to

110)

.

TEA

10

0 0.

1 m

l o

f te

st

ma

teria

l w

as

pla

ce

d

insid

e

the

lo

we

r e

yelid

. Li

ds

we

re

he

ld t

og

eth

er

for

a f

ew

se

co

nds.

Eye

s w

ere

e

xam

ine

d

at

1,

24,

an

d

72

hour

s a

nd

7 d

ays

aft

er

ap

plic

a-

tion.

Sc

orin

g

wa

s a

cc

ord

ing

to

the

sca

le o

f D

raiz

e

et

al.i

’Prr

(sc

ale

=

0

to

110)

.

Rab

bits

Rab

bits

Rab

bits

6 ra

bb

its

at

ea

ch

do

se

leve

l

6 m

ale

rab

bits

Mo

de

rate

p

ain

an

d s

we

llin

g

in

un

wa

she

d

171

eye

. Sl

ight

c

on

jun

ctiv

al

irrita

tion

w

hic

h

sub

side

d

in 4

8 h.

N

o

irrita

tion

o

bse

rve

d

in t

he

wa

she

d

eye

. “S

light

to

m

od

era

tely

irrita

ting

, no

co

rne

a1

da

ma

ge

lik

ely

.”

Esse

ntia

lly

no i

rrita

tion

o

bse

rve

d

in w

ash

ed

17

1

or

un

wa

she

d

eye

s.

0.00

5 m

l yi

eld

ed

a

sc

ore

o

f ~5

.0,

0.02

m

l 18

5

yie

lde

d

a s

co

re

of

>5.0

. 5.

0 is

the

le

vel

rep

rese

nta

tive

o

f se

vere

in

jury

; n

ec

rosis

visi

ble

a

fte

r st

ain

ing

a

nd

co

verin

g

- 75

%

of

the

su

rfa

ce

o

f th

e c

orn

ea

.

0.01

m

l g

ave

a 0

sc

ore

o

n a

ll d

ays

eye

s 18

7

we

re

exa

min

ed

. 0.

03

ml

ga

ve a

sc

ore

o

f

1 o

n D

ay

1 a

nd

0 t

here

aft

er.

0.10

m

l

yie

lde

d

a s

co

re

of

4 o

n D

ay

1, 2

on

Da

ys

3 a

nd

7,

an

d 0

on

Da

ys

14

an

d 2

1.

The

m

ed

ian

nu

mb

er

of

da

ys f

or

eye

s to

retu

rn

to

no

rma

l w

as

1 fo

r 0.

01

an

d

0.03

m

l a

nd

3 f

or

0.10

m

l.

Eye

irri

tatio

n

sco

res

rang

ed

fro

m

O-1

0 fo

r 17

2

24

lab

ora

torie

s.



TAB

LE

7.

(Co

ntin

ue

d.)

Co

nce

ntra

tion

Ma

teria

l te

ste

d

PM

DEA

, 99

+ p

erc

ent

30

in

wa

ter

DEA

, 99

+ p

erc

ent

50

in

wa

ter

Me

tho

d

ml

of

test

m

ate

rial

wa

s p

lac

ed

into

th

e

co

nju

nc

tiva

l sa

c o

f th

e

rab

bit

eye

an

d a

llow

ed

to

re

ma

in

for

15

sec

. Th

e

eye

wa

s rin

sed

.

No

. a

nd

spe

cie

s

of

an

ima

ls

6 ra

bb

its

6 ra

bb

its

Resu

lts

The

m

ate

rial

wa

s e

sse

ntia

lly

noni

rrita

ting

to t

he e

ye.

“No

nco

rrosiv

e

to e

ye”.

Mo

de

rate

to

se

vere

c

on

jun

ctiv

al

irrita

tion

an

d c

orn

ea

1 in

jury

w

ith

slig

ht

red

de

nin

g

of

the

iri

s w

as

ob

serv

ed

. Th

e

eye

ess

en

tially

h

ea

led

in

7

da

ys.

“Se

vere

Ref.

174

174

DEA

10

0 Ra

bb

its

185

irrita

nr.

0.00

5,

0.02

m

l o

f te

st

ma

teria

l

ap

plie

d

to c

orn

ea

1 c

ent

er

wh

ile

eye

lids

are

re

tra

cte

d.

Lid

s re

lea

sed

aft

er

1 m

in.

Eye

in

jury

sc

ore

d

on

a

sca

le o

f 0

to 2

0 p

oin

ts

aft

er

18 t

o

24

hour

s.

0.00

5 m

l yi

eld

ed

a

sc

ore

o

f ~5

.0,

0.02

yie

lde

d

a s

co

re

of

~5.0

. 5.

0 is

the

le

vel

rep

rese

nta

tive

o

f se

vere

in

jury

; n

ec

rosis

visi

ble

a

fte

r st

ain

ing

a

nd

co

verin

g

- 75

pe

rce

nt

of

the

su

rfa

ce

o

f th

e c

orn

ea

.

____

____

____

____

____

____

____

____

____

____

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

MEA

, 99

+ p

erc

ent

30

in

wa

ter

-0.2

m

l o

f te

st

ma

teria

l w

as

pla

ce

d

6 ra

bb

its

Slig

ht

disc

om

fort

, sli

ght

c

on

jun

ctiv

al

irrita

- 17

7

into

th

e

co

nju

nc

tiva

l sa

c o

f th

e

tion,

a

nd

slig

ht

co

rne

a1

clo

ud

ing

w

hic

h

rab

bit

eye

an

d a

llow

ed

to

re

ma

in

he

ale

d i

n 4

8 ho

urs

wa

s o

bse

rve

d.

for

15

sec

. Th

e

eye

wa

s rin

sed

. “M

od

era

tely

irr

itatin

g.”

MEA

1,

5,10

0 0.

005

ml

of

un

dilu

ted

o

r d

ilute

d

test

Ra

bb

its

1%

solu

tion

yie

lde

d

a s

co

re

I 5.

0;

5 a

nd

18

5

ma

teria

l a

pp

lied

to

co

rne

a1

ce

nte

r 10

0%

solu

tions

yi

eld

ed

sc

ore

s >5

.0.

wh

ile

lids

are

re

tra

cte

d.

Lid

s 5.

0 is

the

le

vel

rep

rese

nta

tive

o

f se

vere

rele

ase

d

aft

er

1 m

in.

Eye

in

jury

in

jury

; n

ec

rosis

vi

sib

le

aft

er

sta

inin

g

an

d

sco

red

o

n a

sc

ale

of

0 to

20

p

oin

ts

co

verin

g

- 75

p

erc

ent

o

f th

e

surf

ac

e

of

aft

er

18

to 2

4 h.

th

e

co

rne

a.

____

____

____

____

____

____

____

____

____

____

----

----

----

----

----

----

----

----

----

----

----

----

----

__

____

____

____

_-__

__--

----

----

--



Sha

mp

oo

(T

EA,

12.6

%)

Ha

ir p

rep

ara

tion

(DEA

, 1.

6%;

MEA

, 5.

9%;

sod

ium

b

ora

te,

3.2%

)

100

of

the

sha

mp

oo

100

of

the

ha

ir

pre

pa

ratio

n

0.1

ml

of

the

sh

am

po

o

wa

s in

still

ed

into

th

e

co

nju

nc

tiva

l sa

c o

f th

e

left

eye

. H

eld

c

lose

d

for

1 se

c.

Aft

er

15

set,

rinse

d

with

50

m

l ta

p

wa

ter.

Eye

s w

ere

e

xam

ine

d

at

24,

48,

an

d 7

2 ho

urs

an

d a

t 4

an

d

7 d

ays

p

ost

-inst

illatio

n.

0.1

ml

of

the

h

air

pre

pa

ratio

n

wa

s

pla

ce

d i

nto

th

e

co

nju

nc

tiva

l sa

c o

f

one

eye

. Th

e

lids

we

re h

eld

to

ge

the

r

for

1 se

c.

Atie

r 30

se

t, th

e

eye

s o

f

3 a

nim

als

we

re

wa

she

d

with

20

m

l

of

de

ion

ize

d

wa

ter.

The

e

yes

we

re

exa

min

ed

a

t 24

, 48

, a

nd

72

hour

s

an

d a

t 4

an

d 7

da

ys a

nd

we

re

sco

red

a

cc

ord

ing

to

the

m

eth

od

o

f

Dra

ize

e

t a

1.r’

“’

(sc

ale

=

0

to

110)

.

6 rh

esu

s Sl

it la

mp

exa

min

atio

ns

at

24

h r

eve

ale

d

188

mo

nke

ys

ed

em

ato

us

co

rne

a

an

d s

light

slo

ughi

ng

of

the

co

rne

a1

ep

ithe

lium

in

the

tre

ate

d

eye

s o

f 2

an

ima

ls.

At

72

h, a

slig

ht

po

sitiv

e

fluo

resc

ein

st

ain

ing

w

as

ob

serv

ed

in t

he e

ye o

f o

ne

mo

nke

y a

nd

at

Da

y 7,

a f

ain

t,

diff

use

p

osit

ive

st

ain

ing

w

as

note

d

in o

ne

mo

nke

y.

9 ra

bb

its

Ma

xim

um

ave

rag

e i

rrita

tion

sc

ore

s fo

r b

oth

19

4

wa

she

d

an

d u

nw

ash

ed

e

yes

wa

s 0.

7.




Vaginal Mucosa Irritation

A spermicidal preparation containing 1.92% TEA was tested for vaginal mucosa irritation using six female rats in the same stage of estrus. A 0.5 ml volume of the ointment was placed inside the vaginas of the rats at a depth of 0.6X1.8 cm daily for three days. On the fourth day, the vaginas were exposed and examined for erythema, exudate, and edema. The researchers classified the spermicidal preparation as a nonirritant to rat vaginal mucosa.(‘Bg)

Inhalation Studies

Respiratory difficulties and some deaths in male rats resulted from the short- term inhalation of 200 ppm DEA vapor or 1400 ppm DEA aerosols. Inhalation of 25 ppm DEA for 216 continuous hours resulted in increased liver and kidney weights. A workday schedule inhalation of 6 ppm DEA for 13 weeks resulted in growth rate depression, increased lung and kidney weights, and some deaths in male rats.(164)

Weeks et aI. reported that the dominant effects of continuous exposure of dogs, guinea pigs, and rats to 5-6 ppm MEA vapor were skin irritation and lethargy. The inhalation of MEA vapor at concentrations of 12-26 ppm for 90 days did not result in any mortality in dogs or rodents. Some deaths did occur after 25 days in dogs exposed to 102 ppm MEA vapor, and after 24-28 days in rodents exposed to 66-75 ppm MEA vapor. Exposure to 66-l 02 ppm MEA vapor caused behavioral changes and produced pulmonary and hepatic inflammation, hepatic and renal damage, and hematologic changes in dogs and rodents.

Parenteral Studies

The mouse acute intraperitoneal LD50s of TEA and MEA have been reported to be 1.450 and 1.050 g/kg, respectively.‘lgl) Blum et al.(l’*) determined that the mouse acute intraperitoneal LD50 of DEA was 2.3 g/kg. This level of DEA produced hepatic steatosis, cellular degeneration and swollen hepatic mitochondria in the 24 h following the injection. After 24 h, survivors were apparently normal. The livers of mice that survived over 48 h appeared to have returned to normal. Other information can be found in the literature on the intraperitoneal administration of the ethanolamines to mice and rats.(164.‘g5,1g6)

SPECIAL STUDIES

Mutagenesis

The Ames assay has been used to investigate the mutagenic potential of the ethanolamines.(‘g7) TEA, 99 + percent, with or without metabolic activation, was not mutagenic at concentrations of 0.001 to 100 mg/plate to Salmonella typhimurium strains TA98, TAlOO, TA1535, TA1537, and TA1538.““) The Na- tional Toxicology Program (NTP) tested O-3.333 mg/plate of TEA and DEA in their preincubated Salmonella mutagenicity assay in strains TA98, TAlOO, TA1535, and TA1537 with and without metabolic activation and reported both




chemicals to be negative. (lgg) Hedenstedt’2”“) tested DEA and MEA with and without metabolic activation by liver preparations from rats induced with a polychlorinated biphenyl mixture in S. typhimurium strains TAl 00 and TA1535. There was no observed increase in the number of mutants per plate with either DEA or MEA.

The mutagenicity of TEA, sodium nitrite, and a mixture of the two, with and without metabolic activation by liver S-9, was tested with Bacillus subtilis. Only the mixture of TEA and sodium nitrite was mutagenic to the bacteria. N-nitrosodiethanolamine (NDELA) was found in this mixture, but NDELA does not in- duce mutations in B. subtilis without metabolic activation. Some other reaction mixture product must be mutagenic and this product loses its mutagenic activity in the presence of liver enzymes.(*O1’

Fresh primary rat hepatocyte cultures were treated simultaneously with TEA and ‘H-thymidine in an unscheduled DNA synthesis test. DNA repair was quan- titated by microautoradiographic evaluation of the incorporation of 3H-thymidine into nuclear DNA. The concentrations of TEA tested ranged from 10-8-10-1 M and three cultures were tested per concentration. The authors reported that TEA did not appear to cause DNA-damage inducible repair.‘*‘*)

Carcinogenesis

Kostrodymova et aI. used a total of 560 male mice, strain CBA X C67Bi6,

in a series of three experiments to study the possible carcinogenic and cocarcinogenic effects of pure TEA, 99+ percent, and industrial TEA, 80+ percent, and the combined effect of TEA and syntanol DC-lo, applied cutaneously. The experiments ran for 14-18 months, and they found no evidence of TEA carcinogenicity or cocarcinogenicity.

Hoshino and Tanooka(*“) fed a diet containg O.Ol%, 0.03%, or 0.3% TEA to groups of 40 ICR-JCL male and 40 ICR-JCL female mice throughout the life-span of the animals. The malignant tumor incidence in females was 2.8%, 27%, and 36%, and in males was 2.9%, 9.1%, and 3.6% for the mice fed diets containing O.O%, 0.03%, and 0.3% TEA, respectively. Treated females showed a much higher incidence of thymic and nonthymic tumors in lymphoid tissues than treated males. The mice fed TEA in their diet survived as long as the control mice.

DEA is currently being tested in an NTP carcinogenesis bioassay program. It is being administered in drinking water to rats and mice.(“‘)

Teratogenesis and Reproduction Studies

Hair dyes containing O.lO%-0.15% TEA, 1.5% TEA, or 2.0% DEA were topically applied to the shaved skin of groups of 20 pregnant rats on Days 1,4, 7, 10, 13, 16, and 19 of gestation. On Day 20, the rats were sacrificed and comparisons were made with control rats. No significant soft tissue or skeletal changes were noted in the fetuses. The mean number of corpora lutea, implantation sites, live fetuses, resorptions per pregnancy, and number of litters with resorptions were not significantly different in the dye-treated and control rats.(l’O)

A composite hair dye and base containing 22% MEA was given to 60 female rats at concentrations of 0 to 7800 ppm in the diet from Day 6 to 15 of gestation.




The rats were sacrificed at Day 19 and there was no evidence of any adverse effects on the rats or their pups. No differences were observed in the average number of implantation sites, live pups, early or late resorptions per litter, or females with one or more resorption sites. Thirty male rats were fed diets containing O-7800 ppm composite for eight weeks prior to mating and during mating to 60 female rats on a basal diet. Sixty female rats were fed O-7800 composite- containing diets eight weeks prior to mating through Day 21 of lactation. They were mated with 30 male rats on the basal diet. In both experimental designs, there were no dose-related significant differences in male and female fertility, length of gestation, number of females with resorption sites, live pups per litter, pup body weights, and pup survival. The composite hair dye and base was also administered at a dose of O-19.5 mg/kg/day by gavage to 48 artificially in- seminated female rabbits from Day 6 to 18 of gestation. The rabbits were sacrificed at Day 30. There was no evidence of any teratologic effects. Fetal survival was not adversely affected and no grossly abnormal fetuses or soft tissue defects were seen.(166)

CLINICAL ASSESSMENT OF SAFETY

Dermal Studies

Patch tests can be used to measure skin irritation and sensitization by a chemical substance in human subjects. However, caution should be exercised in the interpretation of patch tests. Patches will elicit positive reactions in cases where the test material is a primary irritant or when the human subject has been sensitized by previous contact with the chemical, either in a past patch or in the course of his daily life. (*03) In addition, patch tests may elicit positive responses because the threshold irritating concentration of a chemical has decreased after repeated exposure of the skin to irritants; this would be a fatigue response. The population from which the subjects are drawn is also important. Certain skin types may be predisposed to react more intensely to chemical insult.(204)

Triethanolamine is the only ethanolamine for which human skin irritation and sensitization data are presented. The results of six patch test experiments with triethanolamine and details of those experiments are presented in Table 8. TEA produced minimal irritation in 1143 “normal” subjects and was more irritating to subjects chosen because they were “hyper reactors” to skin irritants or because they were suffering from eczema.

The cosmetic industry has conducted studies on the skin irritation, sensitization, and photosensitization of a variety of products containing the ethanolamines. Data from these unpublished experiments are presented in Table 9. There was some evidence of irritation by some products.

Inhalation Studies

MEA inhalation by humans has been reported to cause immediate allergic responses of dyspnea and asthma(205) damage and chronic hepatitis.(‘6g)

and clinical symptoms of acute liver



TAB

LE

8.

Skin

Irr

itatio

n a

nd

Se

nsiti

zatio

n b

y Tr

ieth

an

ola

min

e.

Ma

teria

l

test

ed

Co

nce

ntra

tion

an

d d

ose

M

eth

od

Num

be

r

of

sub

jec

ts

Resu

lts

Ref.

TEA

, 88

.6%

0.

5 m

l o

f 1%

(DEA

, 6%

) a

ctiv

e T

EA

TEA

5%

TEA

2%

in

wa

ter

TEA

TEA

5 %

in

pe

tro

latu

m

100%

; 10

a

nd

5%

in

eth

ano

l

TEA

5%

, 1%

in

eu

ce

rin

with

wa

ter

24

h s

em

ioc

clu

sive

in

duc

tion

p

atc

hes

we

re

ap

plie

d

on

the

d

ors

al

surf

ac

e

of

the

u

pp

er

arm

3

time

s p

er

we

ek

for

3 w

ee

ks.

14

da

ys

late

r, c

ha

llen

ge

pa

tche

s w

ere

a

pp

lied

to

the

sa

me

site

a

nd

the

o

the

r a

rm

an

d t

hese

we

re

gra

de

d a

t 48

a

nd

96

h o

n a

sca

le o

f O

-6.

Patc

h te

st,

1979

-l 98

0

Patc

h te

sts,

19

74-1

976,

M

ars

eill

e,

Fra

nc

e

Patc

h te

sts

Test

m

ate

rial

ap

plie

d

in a

n a

lum

inu

m

cha

mb

er

co

nta

inin

g

a c

ott

on

disk

onc

e d

aily

fo

r 3

da

ys,

aft

er

light

sca

rific

atio

n

of

the

fo

rea

rm

site

w

ith

a n

ee

dle

. Re

ad

ing

s o

n a

sc

ale

of

O-4

a

t 72

h

30

min

a

fte

r c

ham

be

r

rem

ova

l.

24

h p

atc

h te

sts.

Re

ad

ing

s a

fte

r 24

a

nd

48

h.

64

479

500

100

5-10

(u

nsp

ec

ifie

d)

Ca

uc

asia

n “

hyp

er

rea

cto

rs”

(ga

ve

bris

k in

flam

ma

tory

rea

ctio

n to

24

h

fore

arm

e

xpo

sure

of

5%

aq

ueo

us

sod

ium

la

ury

l

sulfa

te

in a

n

alu

min

um

cha

mb

er.)

22

sub

jec

ts

suff

erin

g

from

d

iffe

rent

typ

es

of

ec

zem

as

No

irr

itatio

n

(0)

in 4

51

ind

uctio

ns.

Mild

irrita

tion

(1

) in

420

a

nd

mo

de

rate

irrita

tion

(2

) in

3 i

nd

uctio

ns

(inc

lud

es

resid

ua

l re

ac

tions

).

188

an

d 6

8 sc

ore

s

of

0 a

nd

1

at

ch

alle

ng

e,

resp

ec

tive

ly.

“No

se

nsiti

zatio

n.“a

9 (2

%)

po

sitiv

e

rea

ctio

ns

for

co

nta

ct

de

rma

titis

ob

serv

ed

. (S

en

sitiz

ing

)

23

(4.6

%)

po

sitiv

e

rea

ctio

ns

for

co

nta

ct

de

rma

titis

ob

serv

ed

. (S

en

sitiz

ing

)

2 p

osit

ive

re

ac

tions

fo

r a

llerg

ic

co

nta

ct

de

rma

titis

we

re

ob

serv

ed

. (S

en

sitiz

ing

)

100%

TE

A

wa

s re

qu

ired

to

p

rod

uce

a

n

irrita

nt

rea

ctio

n o

n n

on

sca

rifie

d

skin

.

10%

TE

A

wa

s a

ma

rke

d

irrita

nt

(2.5

-

4.0)

a

nd

pus

tule

s w

ere

o

bse

rve

d

an

d

5%

TEA

w

as

a s

light

irr

itant

(0

.5-l

.4)

on

sca

rifie

d

skin

.

4 a

nd

3 p

osit

ive

re

ac

tions

to

5%

a

nd

1%

TEA

, re

spe

ctiv

ely

. (Ir

rita

ting

)

214

215

21’6

217

218

219

aC

onc

Iusio

ns

of

the

re

sea

rche

rs

are

in

quo

tatio

ns.

Inte

rpre

tatio

ns

of

the

Ex

pe

rt

Pan

el

are

in

p

are

nthe

ses.



TAB

LE

9.

Skin

Ir

rita

tion

, Se

nsi

tiza

tion

, Ph

oto

toxi

city

, a

nd

Ph

oto

sen

sitiz

atio

n

by

Pro

du

cts

C

on

tain

ing

th

e

Eth

an

ola

min

es.

Ma

teria

l te

ste

d

Co

nce

ntra

tion

an

d d

ose

M

eth

od

Num

be

r

of

sub

jec

ts

Resu

lts

Ref.

Sha

vin

g

pre

pa

ratio

n

100%

2

24-h

our

p

atc

hes

ap

plie

d

10 t

o

14

da

ys

508

46

we

ak

(no

nve

sicu

lar)

(+

) re

ac

tions

to

the

(T

EA,

4.2%

) a

pa

rt o

n th

e

sam

e s

ite.(

z031

Sim

ulta

neo

us

first

c

lose

d

pa

tch,

42

+

a

nd

7 s

tro

ng

clo

sed

p

atc

h o

n b

ac

k a

nd

op

en

pa

tch

(ed

em

ato

us

or

vesic

ula

r)

(+

+)

rea

ctio

ns

on

arm

. Sc

orin

g

sca

le w

as

+

to

to t

he

sec

ond

clo

sed

p

atc

h. 6

7 +

re

ac

tions

+

+

+

.r1

20)

Ad

diti

on

ally

, th

ere

w

as

UV

a

fte

r U

V

(Ha

no

via

Ta

nett

e

Ma

rk

1 la

mp

, e

xpo

sure

o

f th

e

sec

ond

p

atc

h.

360

nm

at

12

in f

or

1 m

in)

exp

osu

re

of

the

se

co

nd

pa

tch.

“N

oni

rrita

ting

.”

(Irr

i-

tatin

g.

Eith

er

mild

ly

pho

toto

xic

o

r U

V

enh

anc

em

ent

o

f a

n i

rrita

tion

re

spo

nse

).a

Sh

avi

ng

p

rep

ara

tion

10

0%

10

24-h

our

in

duc

tion

p

atc

hes

with

24

-ho

ur

260

Betw

ee

n

31

an

d 6

4 +

re

ac

tions

w

ere

(T

EA,

4.2%

) re

cup

era

tive

p

erio

ds

in

be

twe

en

. A

fte

r o

bse

rve

d

to c

lose

d

ind

uctio

n

pa

tche

s 2

to

3 w

ee

ks

rest

, a

48-

hour

c

ha

llen

ge

1

thro

ugh

10.

1,3,

3,4,

a

nd

4 s

tro

ng

+ +

pa

tch

(mo

difi

ca

tion

o

f Re

f. 22

1).

Sim

ul-

rea

ctio

ns

to c

lose

d

ind

uctio

n

60

+

an

d

tane

ous

c

lose

d

pa

tch

on

ba

ck

an

d o

pe

n 2

+

+

rea

ctio

ns

to t

he

clo

sed

c

ha

llen

ge

pa

tch

on

arm

. Sc

orin

g

sca

le w

as

+

to

pa

tch.

Fo

llow

ing

U

V

(Ha

no

via

Ta

nett

e

+

+

+ .

(“O

1 A

dd

itio

na

lly,

the

re

wa

s U

V

Ma

rk

1 la

mp

, 36

0 nm

a

t 12

in

ch

es

for

exp

osu

re

of

ind

uctio

n

pa

tche

s 1,

4,7,

a

nd

1

min

.)

exp

osu

re,

7,6,

1,4,

a

nd

8

+

10,

an

d t

he

ch

alle

ng

e

pa

tch.

re

ac

tions

w

ere

o

bse

rve

d

at

ind

uctio

n

pa

tche

s 1,

4,7,

a

nd

10

, a

nd

the

ch

alle

ng

e

pa

tch,

re

spe

ctiv

ely

. “N

ons

ens

itizi

ng

an

d

nonp

hoto

sens

itizi

ng.”

(Ir

rita

ting

) Sh

avi

ng

p

rep

ara

tion

N

orm

al

use

U

sed

o

n th

e

fac

e f

or

4 w

ee

ks

an

d s

co

red

52

m

ale

N

o

rea

ctio

ns

we

re

ob

serv

ed

. “N

oni

rrita

ting

.”

(TEA

, 4.

2%)

ea

ch

we

ek.

Sun

cre

am

lO

O%

, 24

-ho

ur

oc

clu

sive

in

duc

tion

p

atc

hes

48

1 b

are

ly

pe

rce

ptib

le

(h)

rea

ctio

n;

min

ima

l (T

EA,

3.75

%)

-0.1

m

l a

pp

lied

to

the

u

pp

er

ba

ck

3 tim

es

a

fain

t (li

gh

t p

ink)

un

iform

o

r sp

ott

y w

ee

k fo

r 3

we

eks

. A

fte

r 2

we

eks

re

st,

a

ery

the

ma

a

t in

duc

tion

p

atc

h 2.

“N

o

24-h

our

o

cc

lusiv

e

ch

alle

ng

e

pa

tch

wa

s p

ote

ntia

l fo

r in

du

cin

g

alle

rgic

ap

plie

d

to a

pre

vio

usl

y un

pa

tche

d

site

. se

nsiti

zatio

n.”

Rea

ctio

ns

we

re

sco

red

24

a

nd

48

hour

s

aft

er

pa

tch

rem

ova

l o

n a

sc

ale

of

0 to

4.

222

222

223

186



Sha

vin

g

cre

am

(TEA

, 3.

3%)

100%

Sha

vin

g

cre

am

(TEA

, 3.

3%)

100%

Sha

vin

g

cre

am

(TEA

, 2.

6%)

100%

Ma

sca

ra

form

ula

tion

loo

%,

0.2

n

(TEA

, 2.

1%)

Ma

sca

ra

form

ula

tion

loo

%,

0.2

m

(TEA

, 2.

1%)

Ma

sca

ra

form

ula

tion

100%

(TEA

, 2.

1%)

Ma

sca

ra

form

ula

tion

100%

(TEA

, 2.

1%)

12-h

our

o

cc

lusiv

e

ind

uctio

n

pa

tche

s

ap

plie

d

to t

he

me

dia

l su

rfa

ce

o

f th

e

up

pe

r a

rm

4 tim

es

a w

ee

k fo

r 2

we

eks

an

d s

co

red

a

t p

atc

h re

mo

val

on

a s

ca

le

of

0 to

4.

Aft

er

2 w

ee

ks

rest

, a

24-

hour

oc

clu

sive

c

ha

llen

ge

p

atc

h w

as

ap

plie

d.

Rea

ctio

ns

we

re

sco

red

a

t 24

, 48

, a

nd

72

hour

s.

!3-h

ou

r p

atc

hes

ap

plie

d

to t

he

ba

ck

eve

ry

da

y fo

r 21

d

ays

. Re

ac

tions

w

ere

sc

ore

d

da

ily

on

a s

ca

le o

f 0

to

4.

48-h

our

o

cc

lud

ed

p

atc

h w

as

ap

plie

d

to

the

a

rm

or

ba

ck;

24

-ho

ur

aq

ueo

us

sod

ium

lau

ryl

sulfa

te

oc

clu

de

d

pa

tch

on

arm

o

r

ba

ck,

the

n 5

alte

rna

te

da

y 48

-ho

ur

oc

-

clu

de

d

pa

tche

s o

f th

e

test

m

ate

rial.

Aft

er

a I

O-d

ay

rest

, 5-

10

pe

rce

nt

sod

ium

la

ury

l

sulfa

te

wa

s a

pp

lied

to

ano

the

r te

st

site

for

1 ho

ur

an

d f

ollo

we

d

by

a 4

8-ho

ur

oc

clu

de

d

pa

tch

of

the

te

st

ma

teria

l.

Rea

ctio

ns w

ere

ob

serv

ed

at

pa

tch

rem

ova

l

an

d 2

4 ho

urs

late

r.

54

57

51

15

15

25

25

5,

16,

an

d 1

4 ve

ry

slig

ht

ery

the

ma

(*

),

slig

ht

ery

the

ma

(l)

, a

nd

we

ll d

efin

ed

e

ryth

em

a

(2)

rea

ctio

ns,

resp

ec

tive

ly,

we

re

ob

serv

ed

to t

he

8 in

duc

tion

p

atc

hes.

N

umb

er

of

po

sitiv

e

rea

ctio

ns

inc

rea

sed

w

ith

ea

ch

ind

uctio

n.

No

re

ac

tions

to

the

ch

alle

ng

e

pa

tch.

(Ir

rita

ting

)

104,

36

, 5,

a

nd

2 s

light

e

ryth

em

a

(l),

mo

de

rate

e

ryth

em

a

(2),

se

vere

e

ryth

em

a

(3),

an

d e

de

ma

with

o

r w

itho

ut

ery

the

ma

(4)

rea

ctio

ns,

resp

ec

tive

ly,

we

re

ob

serv

ed

to t

he 8

in

duc

tion

p

atc

hes.

N

umb

er

of

po

sitiv

e

rea

ctio

ns

ge

ne

rally

in

cre

ase

d

with

ea

ch

in

duc

tion

. 6

1 +

a

nd

1 2

+

rea

ctio

ns

we

re

ob

serv

ed

o

n c

ha

llen

ge

a

t 24

ho

urs.

At

48

hour

s,

4 1

+

an

d

1 2+

re

ac

tions

we

re

ob

serv

ed

, a

nd

at

72

hour

s,

2 1

+

rea

ctio

ns

we

re

ob

serv

ed

. (Ir

rita

ting

)

27

slig

ht

ery

the

ma

(1

) a

nd

1 m

od

era

te

ery

the

ma

(2

) re

ac

tions

w

ere

o

bse

rve

d

to

the

8

ind

uctio

n

pa

tche

s.

1 1

+

rea

ctio

n

wa

s o

bse

rve

d

on

ch

alle

ng

e

at

24

hour

s.

(Mild

ly

Irrita

ting

)

7,

42,

2,

an

d 3

que

stio

na

ble

e

ryth

em

a

(*),

ery

the

ma

(l)

, e

ryth

em

a

an

d p

ap

ule

s (2

),

an

d e

ryth

em

a,

pa

pu

les,

ve

scic

les,

a

nd

po

ssib

ly

ed

em

a (

3) r

ea

ctio

ns,

resp

ec

tive

ly,

to t

he

21

pa

tche

s.

(Irrit

atin

g)

5,

54,

an

d 6

*,

1,

an

d 2

re

ac

tions

, re

spe

c-

tive

ly,

to t

he

21

pa

tche

s.

(Irrit

atin

g)

No

re

ac

tions

o

bse

rve

d

to c

ha

llen

ge

. “N

o

sens

itiza

tion.

”

No

re

ac

tions

o

bse

rve

d

to c

ha

llen

ge

. “N

o

sens

itiza

tion.

”

224

225

226

227

227

228

229



Y

co

TAB

LE

9.

(Co

ntin

ue

d.)

Ma

teria

l te

ste

d

Co

nce

ntra

tion

an

d d

ose

M

eth

od

Num

be

r

of

sub

jec

ts

Resu

lts

Ref.

Sunt

an

lotio

n

(TEA

, 1.

0%)

100%

Ma

sca

ra

loo

%,

-0.1

CTE

A,

20.0

4%)

ml/

cm

*

Ma

sca

ra

lOO

%,

-0.1

(TEA

, 2.

8%)

ml/

cm

’

48-h

our

o

cc

lusiv

e

ind

uctio

n

pa

tche

s w

ere

ap

plie

d 3

tim

es

a w

ee

k fo

r a

to

tal

of

10 t

ime

s.

Patc

hes

1,5,

6,

an

d 7

we

re o

n

the

le

ft s

ho

uld

er,

the

oth

ers

o

n th

e r

ight

.

The

sit

es

we

re s

co

red

24

to 4

8 ho

urs

aft

er

pa

tch

rem

ova

l. A

fte

r 8

da

ys r

est

, a

ch

alle

ng

e p

atc

h w

as

ap

plie

d t

o a

virg

in

ba

ck

site

an

d s

co

red

24

hour

s a

fte

r

pa

tch

rem

ova

l. Th

e

skin

sit

es

wh

ere

pa

tche

s 1,

4,7,

a

nd

10

an

d t

he c

ha

llen

ge

pa

tch

ha

d b

ee

n w

ere

exp

ose

d t

o U

V

light

(H

an

ovi

a

Tane

tte

M

ark

I

Lam

p)

at

a

dist

anc

e o

f 12

in

ch

es

for

1 m

in

an

d

sco

red

48

hour

s la

ter.

26 f

em

ale

5 tim

es/

we

ek

for

3 w

ee

ks,

du

plic

ate

24-h

our

o

cc

lusiv

e

ind

uctio

n

pa

tche

s

ap

plie

d

to t

he

ba

ck.

The

n,

one

sit

e

an

d

a c

ont

rol

site

(n

o t

est

p

rod

uct)

irr

ad

iate

d

with

3

time

s th

e

ind

ivid

ua

l’s

“min

ima

l

ery

the

ma

d

ose

” (M

ED)

usin

g

a. X

eno

n 26

fe

ma

le

arc

so

lar

simul

ato

r (2

90-4

00

nm).

48

hour

s la

ter,

bo

th

site

s.w

ere

re

ad

.

The

re

wa

s a

lo

-da

y re

st

an

d t

hen,

du

plic

ate

c

ha

llen

ge

p

atc

hes

we

re

ap

plie

d

23

at

fre

sh

site

s.

24

hour

s la

ter

one

sit

e

an

d a

co

ntro

l sit

e

exp

ose

d

to

3 m

in.

of

irra

dia

tion

fro

m

the

so

lar

simul

ato

r

(Sc

hott

W

345

filte

r).

Site

s g

rad

ed

at

15,

_ 24

, 48

, a

nd

72

hour

s a

fte

r lig

ht

exp

osu

re.

No

re

ac

tions

ob

serv

ed

. “N

ot

a p

hoto

-

toxi

ca

nt.”

230

2 sli

ght

re

ac

tions

up

on

c

ha

llen

ge

to

te

st

pro

duc

t a

lon

e.

On

e

do

ubtf

ul

an

d o

ne

ery

the

ma

re

ac

tion

be

fore

irr

ad

iatio

n.

“No

sens

itiza

tion.

” (Ir

rita

tion

)

No

re

ac

tions

o

bse

rve

d.

“No

t p

hoto

toxi

c

or

ph

oto

alle

rge

nic

.”

231

232



Skin

lo

tion

1 O

O%

,

(TEA

, 0.

83%

) -0

.2

ml

Skin

lo

tion

lO

O%

,

(TEA

, 0.

83%

) -0

.2

ml

Skin

lo

tion

1 O

O%

,

(TEA

, 0.

83%

) -0

.2

ml

Skin

lo

tion

1 OO%

,

(TEA

, 0.

83%

) -0

.2

ml

r Site

s o

n b

oth

fo

rea

rms

we

re t

ap

e-s

trip

pe

d

seve

ral

time

s.

Dup

lica

te

24-h

our

o

cc

lu-

sive

p

atc

hes

ap

plie

d

to e

ac

h f

ore

arm

.

The

n,

one

sit

e

irra

dia

ted

w

ith

UV

lig

ht

for

15

min

. a

t a

dist

anc

e

of

- 10

c

m

(-4,

400

CW

lcm

’ U

VA

).

Site

s sc

ore

d

aft

er

pa

tch

rem

ova

l, a

fte

r irr

ad

iatio

n,

an

d 2

4 a

nd

48

hour

s a

fte

r irr

ad

iatio

n.

Exa

min

ed

fo

r ta

nnin

g

aft

er

1 w

ee

k.

_ Sc

ore

d

on

a s

ca

le o

f O

-4.

24-h

our

o

cc

lusiv

e

ind

uctio

n

pa

tche

s w

ere

ap

plie

d

3 tim

es

a w

ee

k to

bo

th

fore

arm

s

for

a t

ota

l o

f 10

tim

es.

A

t th

e

en

d o

f

24

hour

s th

e

site

s w

ere

sc

ore

d

an

d

1 sit

e

wa

s irr

ad

iate

d

with

no

nery

thro

ge

nic

U

V

rad

iatio

n

for

15

min

. a

t a

dist

anc

e

of

10 c

m

(-4,

400

pW

lcm

’ U

VA

) a

nd

the

n

sco

red

a

ga

in.

Aft

er

10 t

o

14 d

ays

re

st,

ch

alle

ng

e

pa

tche

s w

ere

a

pp

lied

to

vi

rgin

ad

jac

ent

sit

es.

24

ho

urs

late

r, th

e

site

s

we

re

sco

red

, 1

site

w

as

irra

dia

ted

a

nd

sco

red

. Th

e

ch

alle

ng

e

site

s w

ere

a

lso

rea

d 4

8 a

nd

72

hour

s la

ter.

Sco

red

o

n a

sca

le o

f O

-4.

10

10

30

30

On

e

sub

jec

t h

ad

min

ima

l e

ryth

em

a

(*)

at

233

bo

th

site

s a

t a

ll re

ad

ing

s e

xce

pt

for

the

irra

dia

ted

sit

e

at

the

24

-ho

ur

be

fore

a

nd

aft

er

irra

dia

tion

re

ad

ing

s.

Ano

the

r su

bje

ct

ha

d m

inim

al

ery

the

ma

(*

) a

t th

e

irra

dia

ted

site

a

t th

e

72-h

our

re

ad

ing

. N

o

tann

ing

wa

s o

bse

rve

d.

“No

t p

hoto

toxi

c.”

(Ir

rita

ting

)

On

e

sub

jec

t h

ad

min

ima

l e

ryth

em

a

(*)

at

234

bo

th

site

s a

t a

ll re

ad

ing

s.

Ano

the

r su

bje

ct

ha

d m

inim

al

ery

the

ma

(*

) a

t th

e

irra

dia

ted

site

a

t th

e 4

8-

an

d 7

2-ho

ur

rea

din

gs.

N

o

tann

ing

w

as

ob

serv

ed

. “N

ot

pho

toto

xic

.”

(Irrit

atin

g)

Am

ong

30

0 in

duc

tion

re

ad

ing

s fo

r th

e

235

no

nirr

ad

iate

d

site

s,

the

re

we

re

13

min

ima

l

ery

the

ma

(*

) a

nd

2 e

ryth

em

a

(1)

rea

din

gs.

The

re

wa

s 1

min

ima

l e

ryth

em

a

(*)

ch

alle

ng

e

rea

din

g

at

48

hour

s.

Am

ong

600

ind

uctio

n

rea

din

gs

for

the

irr

ad

iate

d

site

s,

the

re

we

re 8

an

d 9

m

inim

al

ery

the

ma

(A)

rea

din

gs

be

fore

a

nd

aft

er

irra

dia

tion

,

resp

ec

tive

ly,

an

d 4

ery

the

ma

(1

) re

ad

ing

s

aft

er

irra

dia

tion

. Th

ere

w

as

1 m

inim

al

ery

the

ma

(*

) re

ad

ing

a

fte

r irr

ad

iatio

n

at

24

hour

s.

“Do

es

not

ind

uc

e

ph

oto

alle

rgy

or

co

nta

ct

alle

rgy.

” (Ir

rita

ting

)

Am

ong

30

0 in

duc

tion

re

ad

ing

s fo

r th

e

236

no

nirr

ad

iate

d

site

s,

the

re

we

re

15

min

ima

l

ery

the

ma

(*

) a

nd

3 e

ryth

em

a

(1)

rea

din

gs.

The

re

we

re

2 m

inim

al

ery

the

ma

( l )

ch

alle

ng

e

rea

din

gs,

o

ne

at

24

an

d o

ne

at

48

hour

s.

Am

ong

60

0 in

duc

tion

s fo

r th

e

irra

dia

ted

sit

es,

th

ere

w

ere

7

an

d

10

min

ima

l e

ryth

em

a

(*)

rea

din

gs

be

fore

an

d a

fte

r irr

ad

iatio

n,

resp

ec

tive

ly,

an

d

5 e

ryth

em

a

(1)

rea

din

gs

aft

er

irra

dia

tion

.

The

re

wa

s o

ne

ery

the

ma

re

ad

ing

(1

) a

fte

r

irra

dia

tion

a

t 24

ho

urs.

“D

oe

s no

t in

du

ce

ph

oto

alle

rgy

or

co

nta

ct

alle

rgy.

” (Ir

rita

ting

)



TAB

LE

9.

(Co

nti

nu

ed.)

# 0

Ma

teria

l te

ste

d

Co

nce

ntra

tion

an

d d

ose

M

eth

od

Num

be

r

of

sub

jec

ts

Resu

lts

Ref.

Sha

vin

g

cre

am

(TEA

, 2.

1%)

Sha

vin

g

cre

am

(TEA

, 2.

4%)

100%

100%

10

48-

to

72-h

our

o

cc

lusiv

e

ind

uctio

n

pa

tch

ap

plic

atio

ns

to t

he

sam

e

site

,

rea

din

gs

be

fore

th

e

ap

plic

atio

n

of

the

suc

ce

ed

ing

p

atc

h, f

ollo

we

d

by

a r

est

pe

riod

o

f a

bo

ut

3 w

ee

ks

an

d t

hen

a f

ina

l

ch

alle

ng

e

pa

tch

on

a f

resh

sit

e.

Mo

difi

ed

Dra

ize

te

st.(

‘93’

Sha

vin

g

cre

am

(TEA

, 2.

1%)

100%

9 a

-ho

ur

“se

mi-o

pe

n”

ind

uctio

n

ap

plic

atio

ns,

sco

red

48

to

72

ho

urs

late

r ju

st

be

fore

ap

plic

atio

n

of

the

ne

xt

pa

tch,

a

2-w

ee

k

rest

fo

llow

ed

b

y c

ha

llen

ge

p

atc

hes

sco

red

at

48

an

d 9

6 ho

urs

aft

er

ap

plic

atio

n.

Ch

alle

ng

e

pa

tche

s w

ere

a

pp

lied

to

the

orig

ina

l a

nd

to

virg

in

site

s.

Rea

ctio

ns

we

re

sco

red

o

n a

sc

ale

of

O-6

.

104

Am

ong

10

40

ind

uctio

n

rea

din

gs,

th

ere

w

ere

23

7

172

f re

ad

ing

s,

11

(1)

rea

din

gs

an

d o

ne

(3)

rea

din

g.

The

re

we

re

16

(?) c

ha

llen

ge

rea

din

gs.

(Ir

rita

ting

)

76

76

Am

ong

68

4 in

duc

tion

re

ad

ing

s th

ere

w

ere

23

8

231,

83

, a

nd

1

rea

ctio

n o

f (1

) (s

light

ery

the

ma

),

(2)

(ma

rke

d

ery

the

ma

) a

nd

(3)

(ery

the

ma

a

nd

pa

pu

les)

, re

spe

ctiv

ely

.

The

re

we

re

28

(l),

4 (2

),

an

d 3

(E)

(e

ryth

em

a

an

d p

oss

ibly

a

lso

ed

em

a)

rea

ctio

ns

upo

n

ch

alle

ng

e

at

the

o

rigin

al

site

a

nd

23

(1)

rea

ctio

ns

at

the

vi

rgin

sit

e

am

ong

30

4

ch

alle

ng

e

rea

din

gs.

“M

od

era

tely

irr

itatin

g

follo

win

g

initi

al

an

d r

ep

ea

ted

ap

plic

atio

n.

Ve

ry

little

c

um

ula

tive

irr

itatio

n.

No

evi

de

nc

e

of

sens

itiza

tion.

” (S

en

sitiz

ing

)

Am

ong

68

4 in

duc

tion

re

ad

ing

s th

ere

w

ere

23

8

222

an

d

101

rea

ctio

ns

of

(1)

an

d (

2),

resp

ec

-

tive

ly.

Am

ong

30

4 c

ha

llen

ge

re

ad

ing

s

the

re

we

re

33,

13,

an

d 2

re

ac

tions

o

f

(l),

(2),

an

d (

E),

resp

ec

tive

ly,

at

the

o

rigin

al

site

a

nd

20,

2,

a

nd

1

rea

ctio

ns

of

(l),

(2)

an

d

(E),

re

spe

ctiv

ely

, a

t th

e

virg

in

site

. “M

od

er-

ate

ly

irrita

ting

fo

llow

ing

in

itia

l a

nd

rep

ea

ted

ap

plic

atio

n.

Ve

ry

little

c

um

ula

tive

irrita

tion.

N

o

evi

de

nc

e

of

sens

itiza

tion.

”

(Se

nsit

izin

g)



Sha

vin

g

cre

am

10

0%

(TEA

, 2.

1%)

0.5

ml

Sha

vin

g

cre

am

(TEA

, 2.

1%)

100%

)

0.5

ml

9 24

-ho

ur

“se

mi-o

pe

n”

pa

tch

ind

uctio

n

ap

plic

atio

ns

sco

red

48

to

72

ho

urs

late

r

just

b

efo

re

ap

plic

atio

n

of

the

ne

xt

pa

tch

a 2

-we

ek

rest

fo

llow

ed

b

y c

ha

llen

ge

pa

tche

s sc

ore

d

at

48

an

d 9

6 ho

urs

aft

er

ap

plic

atio

n.

Ch

alle

ng

e

pa

tche

s w

ere

ap

plie

d

to

orig

ina

l a

nd

virg

in

site

s.

Rea

ctio

ns

we

re

sco

red

o

n a

sc

ale

of

O-6

.

63

63

Am

ong

56

7 in

duc

tion

re

ad

ing

s,

the

re

we

re

239

106,

4,

2,

a

nd

4

rea

ctio

ns

of

1, 2

, 3

an

d 4

(ery

the

ma

, e

de

ma

, a

nd

pa

pu

les)

, re

spe

c-

tive

ly.

Am

ong

25

2 c

ha

llen

ge

re

ad

ing

s

the

re

we

re

28,

6,

1, 9

, a

nd

1

rea

ctio

ns

of

1, 2

, 3,

4,

a

nd

6

(str

ong

re

ac

tion

spre

ad

ing

be

yon

d

test

sit

e),

re

spe

ctiv

ely

, a

t th

e

orig

-

ina

l sit

e

an

d 9

, 4,

a

nd

2

rea

ctio

ns

of

1,

2,

an

d 3

, re

spe

ctiv

ely

, a

t th

e

virg

in

site

. Sl

ight

irrita

tion

re

sulte

d

from

in

itia

l a

pp

lica

tion

an

d i

nc

rea

ses

in

irrita

tion

w

ere

o

bse

rve

d

follo

win

g

rep

ea

ted

ap

plic

atio

n.

Seve

ral

mo

de

rate

ly

stro

ng

rea

ctio

ns

we

re

ob

serv

ed

wh

en

c

ha

llen

ge

sit

es

we

re

sco

red

a

t

48

hour

s b

ut

in a

ll c

ase

s,

the

re

wa

s m

ark

ed

rem

issio

n

of

rea

ctio

n se

verit

y w

he

n

sco

red

at

96

hour

. “P

roa

bly

sk

in

fatig

ue.”

A

mo

ng

567

ind

uctio

n

rea

din

gs,

th

ere

w

ere

23

9

144,

20

, 8,

a

nd

12

re

ac

tions

o

f 1,

2,

3,

an

d 4

, re

spe

ctiv

ely

. A

mo

ng

252

ch

alle

ng

e

rea

din

gs,

th

ere

w

ere

42

, 8,

5,

19

, a

nd

1

rea

ctio

ns

of

1, 2

, 3,

4,

a

nd

6,

resp

ec

tive

ly,

at

the

o

rigin

al

site

a

nd

19

, 8,

a

nd

2

rea

ctio

ns

of

1,

2,

an

d 4

, re

spe

ctiv

ely

, a

t

the

vi

rgin

sit

e.

Slig

ht

irrita

tion

re

sulte

d

from

in

itia

l a

pp

lica

tion

a

nd

in

cre

ase

s in

irrita

tion

w

ere

o

bse

rve

d

follo

win

g

rep

ea

ted

ap

plic

atio

n.

Seve

ral

mo

de

rate

ly

stro

ng

rea

ctio

ns

we

re

ob

serv

ed

w

he

n

ch

alle

ng

e

site

s w

ere

sc

ore

d

at

48

hour

s b

ut

in

all

ca

ses,

th

ere

w

as

ma

rke

d

rem

issio

n

of

rea

ctio

n se

verit

y w

he

n

sco

red

a

t 96

ho

urs.

“Pro

ba

bly

sk

in

fatig

ue.”



TABL

E‘9.

(C

on

tinu

ed

.) Co

nce

ntra

tion

Num

be

r

Ma

teria

l te

ste

d

an

d d

ose

M

eth

od

o

f su

bje

cts

Re

sults

Re

f.

Sha

vin

g

cre

am

1 O

O%

,

(TEA

, 2.

1%)

0.5

ml

Sha

vin

g

cre

am

(TEA

, 2.

1%)

Sha

vin

g

cre

am

(TEA

, 2.

6%)

Sha

vin

g

cre

am

(TEA

, 2.

1%)

Sha

vin

g

cre

am

(TEA

, 2.

1%)

Sha

vin

g

cre

am

(TEA

, 1.

9%)

100%

100%

100%

100%

100%

Eve

rv

oth

er

da

v fo

r a

to

tal

of

20

da

vs

(ld

op

en-

pa

tch

ap

plic

atio

ns)

a

1 i

n.

squa

re

of

ga

uze

w

as

dip

pe

d

in s

am

ple

an

d a

pp

lied

to

the

su

bje

cts

’ a

rm

(the

sam

e

site

w

as

use

d

ea

ch

tim

e).

24

ho

urs

aft

er

ap

plic

atio

n

the

sit

es

we

re

sco

red

.

A

lo-d

ay

rest

w

as

follo

we

d

by

a c

ha

l-

leng

e

op

en

pa

tch

wh

ich

w

as

ob

serv

ed

24

an

d 4

8 ho

urs

late

r. Re

ac

tions

w

ere

sco

red

o

n a

sc

ale

of

+ 1

to

+4

.

60

60

60

60

60

63

Am

ong

56

7 in

duc

tion

re

ad

ing

s,

the

re

we

re

239

131,

23

, 2,

a

nd

14

re

ac

tions

o

f 1,

2,

3,

an

d 4

, re

spe

ctiv

ely

. A

mo

ng

252

ch

alle

ng

e

rea

din

gs,

th

ere

w

ere

34

, 16

, 6,

18

, a

nd

1

rea

ctio

ns

of

1, 2

, 3,

4,

a

nd

6

resp

ec

tive

ly,

an

d

19,

5,

1, a

nd

1

rea

ctio

ns

of

1, 2

, 3,

an

d 4

, re

spe

ctiv

ely

, a

t th

e v

irgin

sit

e.

Slig

ht

irrita

tion

re

sulte

d

from

in

itia

l

ap

plic

atio

n

an

d i

nc

rea

ses

in

irrita

tion

we

re

ob

serv

ed

fo

llow

ing

re

pe

ate

d a

pp

li-

ca

tion.

Se

vera

l m

od

era

tely

st

rong

re

ac

tions

we

re

ob

serv

ed

w

he

n

ch

alle

ng

e

site

s w

ere

sco

red

a

t 48

ho

urs

but

in

all

ca

ses,

th

ere

wa

s m

ark

ed

re

miss

ion

o

f re

ac

tion

seve

rity

wh

en

sc

ore

d

at

96

hour

s.

“Pro

ba

bly

sk

in

fatig

ue.”

Am

ong

60

0 in

duc

tion

a

nd

12

0 c

ha

llen

ge

24

0

rea

din

gs,

th

ere

w

ere

no

re

ac

tions

. “S

hort

-

live

d

ac

ute

irr

itatio

n,

no s

ens

itiza

tion.

”

Am

ong

60

0 in

duc

tion

re

ad

ing

s th

ere

w

ere

24

0

5 (1

+)

(mild

e

ryth

em

a)

rea

ctio

ns.

The

re

we

re

no c

ha

llen

ge

re

ac

tions

. “S

ho

rt-li

ved

ac

ute

irri

tatio

n,

no s

ens

itiza

tion.

”

Am

ong

60

0 in

duc

tion

re

ad

ing

s th

ere

w

ere

24

0

5 (1

+)

rea

ctio

ns.

The

re

we

re

no c

ha

llen

ge

rea

ctio

ns.

“Sh

ort

-live

d

ac

ute

irri

tatio

n,

no

sens

itiza

tion.

”

Am

ong

60

0 in

duc

tion

re

ad

ing

s,

the

re

we

re

240

3 (1

+)

rea

ctio

ns.

The

re

we

re

no c

ha

llen

ge

rea

ctio

ns.

“Sh

ort

-live

d

ac

ute

irri

tatio

n,

no

sens

itiza

tion.

”

Am

ong

60

0 in

duc

tion

re

ad

ing

s,

the

re

wa

s 24

0

1 (1

+)

rea

ctio

n.

The

re

we

re

no c

ha

llen

ge

rea

ctio

ns.

“Sh

ort

-live

d

ac

ute

irri

tatio

n,

no

sens

itiza

tion.

”



Sha

vin

g

cre

am

(TEA

, 2.

3%)

Suns

cre

en

pro

duc

t

(TEA

, 0.

45%

)

Suns

cre

en

pro

duc

t

(TEA

, 0.

45%

)

Suns

cre

en

pro

duc

t

(TEA

, 0.

45%

)

Sha

vin

g

cre

am

(TEA

, 2.

4%)

Sha

vin

g

cre

am

(TEA

, 2.

1 %

)

100%

1 OO

%,

-0.2

g

1 O

O%

,

-0.2

g

lOO

%,

-0.2

g

10

24-h

our

o

cc

lusiv

e

pa

tch

ap

plic

atio

ns

with

24

- to

48-

hour

re

st

pe

riod

s in

be

twe

en

. Si

tes

sco

red

ju

st

prio

r to

ne

xt

pa

tch

ap

plic

atio

n.

An

1 l-

to

1 S-

da

y re

st

follo

we

d

by

a 2

4-ho

ur

ch

alle

ng

e

pa

tch

on

a v

irgin

sit

e.

Site

s sc

ore

d

at

24

an

d

48

hour

s a

fte

r a

pp

lica

tion

, Sc

ore

d

on

a

sca

le o

f O

-4.

Fore

arm

s w

ere

ta

pe

-str

ipp

ed

to

re

mo

ve

co

rnifi

ed

e

pith

eliu

m.

24-h

our

o

cc

lusiv

e

pa

tch

ap

plic

atio

ns

to

bo

th

arm

s,

pa

tche

s

rem

ove

d,

site

s sc

ore

d,

an

d o

ne

site

sub

jec

ted

to

15

m

inut

es

of

UV

lig

ht

(-

4,40

0 ~W

lcm

’ U

VA

) a

t a

dist

anc

e

of

10

cm

an

d r

est

ore

d.

Ad

diti

on

al

rea

din

gs

we

re

ma

de

48

an

d 9

6 ho

urs

aft

er

ap

plic

atio

n.

Sco

red

o

n a

sc

ale

of

O-4

.

10

24-h

our

o

cc

lusiv

e

pa

tch

+pp

lica

tion

s

to

bo

th

arm

s w

ith

24-

to M

I-ho

ur

rest

pe

riod

s in

b

etw

ee

n.

Site

s sc

ore

d

at

pa

tch

rem

ova

l a

nd

the

n irr

ad

iate

d

for

15

min

at

a d

ista

nce

o

f 10

c

m

(-4,

400

pW

/cm

*

UV

A)

an

d r

e-s

co

red

. A

n 1

l-. t

o

1 S-

da

y

rest

p

erio

d,

24-h

our

c

ha

llen

ge

s to

.virg

in

site

s,

pa

tche

s re

mo

ved

a

nd

site

ssc

ore

d,

irra

dia

ted

, sc

ore

d

ag

ain

an

d s

co

red

24

an

d 4

8 ho

urs

late

r. Sc

ore

d

on

a s

ca

le o

f

o-4

.

lOO

%,

-0.1

ml/

cm

2 10

48

- to

72

-ho

ur

no

no

cc

lusiv

e

ind

uctio

n

r p

atc

h a

oo

lica

tion

s.

Site

s sc

ore

d

at

pa

tch

. . 1

rem

ova

l. 10

th

pa

tch

also

sc

ore

d

24

hour

s

late

r, 1

l-da

y re

st

pe

riod

, fo

llow

ed

b

y a

48-h

our

c

ha

llen

ge

p

atc

h to

a v

irgin

sit

e.

Ch

alle

ng

e

site

sc

ore

d

at

pa

tch

rem

ova

l

an

d 2

4 ho

urs

late

r.

lOO

%,

-0.1

ml/

cm

’

60

52

10

26

100

100

Am

ong

60

0 in

duc

tion

re

ad

ing

s th

ere

w

ere

24

0

2 (1

+)

rea

ctio

ns.

The

re

we

re

no c

ha

llen

ge

rea

ctio

ns.

“Sh

ort

-live

d

ac

ute

irri

tatio

n,

no

sens

itiza

tion.

”

Am

ong

52

0 in

duc

tion

re

ad

ing

s,

the

re

we

re

7 &

(m

inim

al

ery

the

ma

) sc

ore

s.

Am

ong

104

ch

alle

ng

e

rea

din

gs,

th

ere

w

ere

2

*

sco

res.

“N

o

irrita

tion

o

r se

nsiti

zatio

n.”

241

The

re

wa

s 1

f re

ac

tion

at

24

hour

s a

nd

24

1

1 *

rea

ctio

n a

t a

noth

er

site

a

fte

r irr

ad

iatio

n

at

24

hour

s.

“No

p

hoto

toxi

c

resp

ons

e.”

Am

ong

26

0 in

duc

tion

re

ad

ing

s o

f th

e

no

n-

241

irra

dia

ted

sit

e,

the

re

we

re

5 *

sco

res.

Am

ong

78

c

ha

llen

ge

re

ad

ing

s,

the

re

we

re

3 *

sco

res.

A

mo

ng

520

ind

uctio

n

rea

din

gs

of

the

irr

ad

iate

d

site

th

ere

w

ere

5

* sc

ure

s

be

fore

a

nd

5 l

sco

res

aft

er

irra

dia

tion

.

Am

ong

10

4 c

ha

llen

ge

re

ad

ing

s,

the

re

we

re

2 +

Z sc

ore

s.

“No

p

ho

toa

llerg

ic

resp

ons

e.”

Am

ong

11

00

ind

uctio

n

rea

din

gs,

th

ere

w

ere

24

2

2 (d

oub

tful

re

ac

tion,

ve

ry

mild

e

ryth

em

a,

ba

rely

e

xce

ed

ing

th

at

of

the

un

tre

ate

d

skin

) re

ac

tions

. Th

ere

w

ere

no

ch

alle

ng

e

rea

ctio

ns.

“No

irr

itatio

n

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tion.

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ong

11

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w

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243

242

243

244

245

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are

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pa

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hese

s.




An eight-year-old female developed a nasal allergic reaction to a detergent containing TEA. The prick test was positive for 10-'-l Om4 M TEA and not for any of the other ingredients in the product. Sneezing was relieved after removal of the detergent from the clothes by extensive washing and recurred upon re-exposure.(206’

Potential hazards from inhalation of TEA and DEA are probably minimized by their low vapor pressures.(“)

Occupational Exposure

Information on vascular, neurologic, and hepatic disorders and respiratory and skin allergies of people who come in contact with the ethanolamines in their work environment can be found in the literature.(207-2’3)

SUMMARY

TEA, DEA, and MEA are amino alcohols and as such, are chemically bifunctional, combining the properties of alcohols and amines. The pHs of 0.1 N aqueous solutions of TEA, DEA, and MEA are 10.5, 11 .O, and 12.05, respectively. Ethanolamine soaps and ethanolamides are used in cosmetic formulations as emulsifiers, thickeners, wetting agents, detergents, and alkalizing agents. In 1981, TEA, DEA, and MEA were reported to be ingredients of 2757, 18, and 51 cosmetic products, respectively. Most products contained TEA, DEA, and MEA in concentrations less than or equal to 5%. The nitrosation of the ethanolamines may result in the formation of N-nitrosodiethanolamine (NDELA) which is carcinogenic in laboratory animals. Traces of NDELA (below 5 ppm) have been found in a variety of cosmetic products.

The LD50 values for rats of TEA, DEA, and MEA ranged from 4.19 g/kg to 11.26 g/kg, 0.71 ml/kg to 2.83 g/kg, and 1.72 g/kg to 2.74 g/kg, respectively. In single-dose oral toxicity for rats, TEA is practically nontoxic to slightly toxic, and DEA and MEA are slightly toxic. Long-term oral ingestion of the ethanolamines by rats and guinea pigs produced lesions limited mainly to the liver and kidney. Long-term cutaneous applications to animals of the ethanolamines also produced evidence of hepatic and renal damage. TEA and DEA showed little potential for rabbit skin irritation in acute and subchronic skin irritation tests. MEA was corrosive to rabbit skin at a 30% concentration in a single semioccluded patch application and at a greater than 10% concentration in 10 open applications over a period of 14 days. A lotion containing 1% TEA was not phototoxic to guinea pigs, and TEA was not a guinea pig skin sensitizer. With long contact time TEA, DEA, and MEA are irritating to the rabbit eye at concentrations of loo%, 50%, and 5%,

respectively. The ethanolamines have been shown to be nonmutagenic in the Ames test

and TEA is also nonmutagenic to Bacillus subtilis. TEA did not cause DNA- damage inducible repair in an unscheduled DNA synthesis test.

TEA had no carcinogenic or cocarcinogenic activity when dermally applied to mice for 18 months. There was a higher incidence of malignant lymphoid tumors in female mice fed diets containing TEA for their whole lifespan than in male mice on the same diet or in control mice.




Clinical skin testing of TEA and cosmetic products containing TEA and DEA showed mild skin irritation in concentrations above 5%. There was very little skin sensitization. There was no phototoxicity and photosensitization reactions with products containing up to 20.04% TEA. A dyeless base formulation containing 11.47% MEA and a hair preparation containing 1.6% DEA and 5.9% MEA were irritating to human skin in patch tests.

COMMENTS

In the presence of N-nitrosating agents, TEA and DEA may give rise to N-nitrosodiethanolamine, a known animal carcinogen.

TEA and DEA are mild skin and eye irritants and irritation increases with increasing ingredient concentration.

Animal studies with MEA indicate that it is both a skin and eye irritant and clinical studies with formulations containing MEA indicate that it is a human skin irritant. The longer MEA stays in contact with the skin the greater the likelihood of irritation. MEA is primarily used in rinse-off hair products.

CONCLUSION

The Panel concludes that TEA, DEA, and MEA are safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of ethanolamines should not exceed 5%. MEA should be used only in rinse-off products. TEA and DEA should not be used in products containing N-nitrosating agents.

ACKNOWLEDGMENT

Ms. Karen Brandt, Scientific Analyst and writer, prepared the literature review and technical analysis used by the Expert Panel in developing this report.

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J .

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L, 61.

lp2,

ti3.

~ 64.

65.

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EDWARDS, G.S., PENG, M., FINE, D.H., SPIEGELHALDER, B., and KAHN, 1. (1979). Detection of N-nitro- Lps. sodrethanolamine in human urine following application of a contaminated cosmetic. Toxicol. Lett. 4,

217-22.

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&--201. HOSHINO, H. and TANOOKA, H. (1978). Carcinogenicity of triethanolamifie in mice and its mutagen-

icity after reaction with sodium nitrite in bacteria. Cancer Res. 38, 3918-21,

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thesis with triethanolamine.*

203. SCHWARTZ, L. and PECK, S.M. (1944). The patch test in contact dermatitis. Public Health Report 59,

546-57.

204. KLIGMAN, A.M. (1978). Cutaheous toxicology: an oVerrle\vfrom the underside. Curr. Probl. Dermatol. 7,

l-25. t

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Immunol. 69, 158.

~207. MADORSKII, V.A. and VORONIN, A.K. (1968). Vascular and neurologic changes in people working with

cooling liquids containing sodium nitrite and triethanolamine. Kazan. Med. Zh. 1, 79-8. /208. PAUSTOVSKAYA, V.V., KRASNYUK, E.P., ONIKIENKO, F.A., and VASILYUK, L.M. (1977). Effect ofwork-

ing conditions on the health of people working with inhibitors of the atmospheric corrosion of metal.

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1/ 209. SELISSKII, G.D., OBUKHOVA, A.S., ANTON’EV, A., SOMOV, B.A., SHAPARENKO, M.V., and

ALCHANGYAN, L.V. (1978). Prophylaxis of occupational dermatoses caused by inhibitors of atmospheric

metal corrosion. Vestn. Dermatol. Venerol. 9, 36-9. (/ 210. SIDORENKO, E.N., BUSLENKO, A.I., BAIDA, N.A., KOtlNtSEVA, P.V., IVANOVA, S.I., DIACHENKO,

E.I., MUKHTAROVA, N.D., and TITENKOV, I.K. (1980). Allergic diseases in workers of rubber produc-

tion. Vrach. Delo 12, 14-6.

V- 211. SIDOROV, K.K. and TIMOFEEVSKAYA, L.A. (1979). Data for substantiation of the maximum possible con-

centrationof monoethanolamine in the working environment. Gig. Tr. Prof. Zabol. 9, 55.

/ 212. TSYRKUNOV, L.P. (1975). Skin diseases in workers contacting with inhibitors of the atmospheric corro-

sion’of metals. Vestn. Dermatol. Venerol. 3, 62-5.

L/ 213. VENEDIKTOVA, K.P., ANTON’EV, A.A., and TUMARKIN, B.M. (1977). Occupational dermatitis and

eczema of finishing-shop textile workers and problems of prophylaxis. Zdravookhr Kaz. 1, 28-31,

A14. CTFA. (May 16, 1974). Submission of data by CTFA. (2-5-56). Human sensitization tests oftriethanolamine

(7406-4) .*

715. NORTH AMERICAN CONTACT DERMATITIS GROUP (NACDG). (Dec. 4, 1980). Standard screening tray

1979 vs. 1980. Summary.

)R16. CALAS, E., CASTELAIN, P.Y., and PIRIOU, A. (1978). Epidemiology of contact dermatitis in Marseilles.

Ann. Dermatol. Venereol. 105, 345-7.

Y 217. FISHER, A.A., PASCHER, F., and KANOF, N.B. (1971). Allergic contact dermatitis due to ingredients of vehicles. A “vehicle tray for patch testing. Arch. Dermatol. 104, 286-90.

w.218. FROSCH, P.J. and KLIGMAN, A.M. (1976). The chamber-scarification test for irritancy. Contact Dermatitis 2, 314-24.

v 219. SUURMOND, D. (1966). Patch test reactions to phenergan cream, promethazine and tri-ethanolamine.

Dermatologica 133, 503-6.

220. WILKINSON, D;>., FREGERT, S., MAGNUSSON, B., BANDMANN, H.J., CALNAN, C.D., CRONIN, E.,

HJORTH, N., MAlBACH, H.J., MALTEN, K.E., MENEGHlNl, C.L., and PIRILA, V. (1970). Terminology of contact dermatitis. Acta Dermatov. 50, 287-92.

221. SHELANSKI, H.A. and SHELANSKI, M.V. (1953). A new technique of human patch tests, Proc. Sci. Sect.

Toil. Goods Assoc. 19, 46-9.




- 222. CTFA. (1977). Submission of data by CTFA. (2-S-9). CIR safety data test summary, human patch test of

shaving preparation containing triethanolamine.*

---223. CTFA. (1978). Submission of data by CTFA. (2-5-10). CIR safety data test summary,human patch test of

shaving preparation containing triethanolamine.’

-224. CTFA. (July 1978). Submission of data by CTFA. (2-S-12). CIR safety data test summary, human patch test

of a shave cream containing triethanolamine.*

-225. CTFA. (July 1978). Submission of data by CTFA. (2-5-14). CIR safety data test summary, human patch test


-226. CTFA. (Sept. 1974). Submission of data by CTFA. (2-5-13). CIR safety data test summary, human patch test


327. FOOD AND DRUG RESEARCH LABORATORIES (FDRL). (Oct. 27, 1976). Submission of data by CTFA.

(2-5-2). Final Report, Clinical safety evaluation of a group of products.*

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appraisal of sensitizing potential of four products by maximization testing, Ivy Prot. No. 3368.*

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four products by maximization testing, protocol No. 3379.’

,230. CTFA. (Oct. 8, 1976). Submission of data by CTFA. (2-s-16). CIR safety data test summary, human patch

test of a suntan lotion containing triethanolamine.*

-231. CTFA. (January 28 to March 21, 1980). Submission of data by CTFA. CIR safety data test summary, human

patch test of mascara containing TEA.*

-232. CTFA. (Sept. 17, 1979). Submission of data by CTFA. CIR safety data test summary, human patch test of

mascara containing TEA.*

a33. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:

854-90A R-2.*

-234. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:

859-72L R-l .*

=?Z35. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:

85490A R-2.*

-236. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:

859-72L R-l .*

~237. CTFA. (Jan. 11, 1971). Submission of data by CTFA. Sensitization studies on products containing

triethanolamine (TEA), products OM-02-N.’

w.238. HTR. (April 26, 1972). Submission of data by CTFA. Sensitization studies on products containing trietha-

nolamine (TEA), product A(1429-152 EHH-60) and B(1429-152 RR-302).*

.... 239. HTR. (Feb. 22, 1973). Submission of data by CTFA. Sensitization studies on products containing

triethanolamine (TEA), products A (EXL-2062, RH-757), B(SR-300, 2103E), and C(SR-347 1506-169).*

m.240. INSTITUTE FOR APPLIED PHARMACEUTICAL RESEARCH (IAPR). (March 27, 1975). Submission of data

by CTFA. Sensitization studies on products containing triethanolamine (TEA), products A (RH-836), B

(RH-757), C (SR-407), D (EHH-259), E (RLH-146) and F (ECH-190-l).*

e.,.241, FDRL. (July 31, 1981). Submission of data by CTFA. Sensitization studies on products containing

triethanolamine (TEA), sunscreen formulation SP 104-L-3-A.*

-242. CTFA. (Jan. 13, 1981). Submission of data by CTFA. Sensitization study on products containing

triethanolamine (TEA), products No. 76 and No. 78, and diethanolamine (DEA), product No. 80.’

~~~243. HTR. (July 7, 1981). Submission of data by CTFA. (2-5-63). Repeated insult patch test, 81-0242-74.’

I-‘-’ 244. HTR. (March 17, 1980). Submission of data by CTFA,, (2-5-8). The study of cumulative irritant properties of

a series of test materials, 8@0192r74.*

45. IRL. (March 31, 1980). Submission of data by CTFA. (2-5-7). The appraisal of the contact-sensitizing poten-

tial of four (4) materials by means of the maximization study, Ivy Research protocol: No. 4308/01.*



Personal Care iProducts CounciCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: Halyna Breslawec, Ph.D.Industry Liaison to the CTR Expert Panel

DATE: September 23, 2011

SUBJECT: Comments on the Draft Report on the MEA Ingredients Prepared for the September 26-27, 2011 CIR Expert Panel Meeting

p.3 - Please revise the following sentence as indicated (add words in brackets). “Accordingly,[products containing] alkyl substituted ethanolamines should be formulated to avoid theformation of nitrosamines.”

p.4 - Where in reference 13 (Hotlist) does it state that Health Canada indicates that Ethanolamine isused up to 10%? If this is strictly a personal communication, it should not be cited to reference13.

p.5 - In the description of the in vitro dermal penetration study of Ethanolamine (reference 16), it is notclear what is meant by “cumulative dose absorbed through the skin”. Is this the material in thereceptor fluid? Or does it also include the material in the skin?

p.7, 12 - What was the exposure duration in the acute inhalation study of the mixture containingethanolamine, hydroxylamine, 1-amino-propano-2-ol, catechol and water (reference 22)?

p.8 - Please correct “mg/kg by/day”p.11 - If there are several in vitro studies examining the ocular irritation potential of Ethanolamine,

why is only one study described?p.11 - The ACGIEI TLV should be cited to ACGIII not OSHA (reference 38).p.13 - In the Summary, please include the concentration tested in the LLNA.p.18 - In the summary of MEA reproductive and developmental toxicity studies, “dye” needs to be

added after “hair”.p.18 - Please provide the range of concentrations of Acetamide MEA and Cocamide MEA tested in the

in vitro genotoxicity assays.p.19 - Please include the concentrations of Acetamide MEA and Cocamide MEA tested in the non

human dermal irritation studies.p.22-29, Tables la and lb - Please provide references for these tables. As this is a review of cosmetic

ingredients, the definitions in the International Cosmetic Ingredient Dictionary and Handbookshould also be given in Table la. For ingredients defined by their structure, it would beappropriate to add a footnote to indicate which ingredients are defined only by their structure inthe Dictionary.

11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



p.34, Table 4a - Footnotes a and b need to be deleted as no uses of these ingredients in deodorant orsuntan products were reported.

p34-, Table 4c - The limit for secondary amine content in the raw materials needs to be changed from5% to 0.5%.

2



Category CAS # Mainterm Count05A - Hair Conditioner 141435 ETHANOLAMINE 1 1305C - Hair Straighteners 141435 ETHANOLAMINE 205D - Permanent Waves 141435 ETHANOLAMINE 605F - Shampoos (non-coloring) 141435 ETHANOLAMINE 205H - Wave Sets* 141435 ETHANOLAMINE 105I - Other Hair Preparations* 141435 ETHANOLAMINE 106A - Hair Dyes and Colors (all types req. caution st 141435 ETHANOLAMINE 731 77206B - Hair Tints 141435 ETHANOLAMINE 2306D - Hair Shampoos (coloring) 141435 ETHANOLAMINE 106F - Hair Lighteners with Color 141435 ETHANOLAMINE 406G - Hair Bleaches 141435 ETHANOLAMINE 606H - Other Hair Coloring Preparation 141435 ETHANOLAMINE 710A - Bath Soaps and Detergents 141435 ETHANOLAMINE 212A - Cleansing 141435 ETHANOLAMINE 1

788

*it is know that this formulation is rinse-off



ETHANOLAMINE 1 05A - Hair Conditioner 13ETHANOLAMINE 1 05C - Hair Straighteners 750ETHANOLAMINE 6 05D - Permanent WavesETHANOLAMINE 2 05F - Shampoos (non-coloring)ETHANOLAMINE 1 05G - Tonics, Dressings, and Other Hair Grooming AidsETHANOLAMINE 1 05H - Wave SetsETHANOLAMINE 1 05I - Other Hair PreparationsETHANOLAMINE 710 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)ETHANOLAMINE 22 06B - Hair TintsETHANOLAMINE 1 06D - Hair Shampoos (coloring)ETHANOLAMINE 4 06F - Hair Lighteners with ColorETHANOLAMINE 6 06G - Hair Bleaches 1ETHANOLAMINE 7 06H - Other Hair Coloring Preparation 763ETHANOLAMINE 1 12A - Cleansing 764

MEA-COCOATE 4 10E - Other Personal Cleanliness Products

MEA-LAURETH SULFAT 1 05F - Shampoos (non-coloring)MEA-LAURETH SULFAT 11 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)MEA-LAURETH SULFAT 1 06H - Other Hair Coloring Preparation

MEA-LAURYL SULFATE 1 01A - Baby ShampoosMEA-LAURYL SULFATE 3 05F - Shampoos (non-coloring)MEA-LAURYL SULFATE 1 10A - Bath Soaps and Detergents

MEA-TALLOWATE 6 10E - Other Personal Cleanliness Products



pink ethanolamine

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